CA2151912A1 - Use of s(+) antipodes of analgesic agents for the manufacture of a composition to treat respiratory disorders - Google Patents

Abstract

The present invention relates to compositions 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 an analgesic agent substantially free or of its R(-) antipode selected from the group consisting of (S+)-ibuprofen, (S+) flurbiprofen and (S+) ketoprofen, pharmaceutically-acceptable salts thereof, and mixtures thereof along with at least one of (a) a decongestant, (b) an expectorant and (c) and antitussive.

Description

. ` ~ WO 94/14476 21$1912 PCT/US93/12022 USE OF S(l) ANTIPODES OF ANALGESIC AGENTS FOR THE MANUFACTURE OF A CoMposITIoN
TO TREAT RESPIRATORY DISORDERS.

TECHNICAL FIELD
The present invention relates to compositions and methods for providing improved treatment, management or mitigation of cold, cold-like ant/or flu symptoms by administering a safe and effective amount of a composition comprising an analgesic agent substantially free or of 1ts R(-) antipode selected from the group consisting of (S~)-ibuprofen, (S+) flurbiprofen and (S~) ketoprofen, pharmaceutically-acceptable salts thereof, and mixtures thereof along with at least one of (a) a decongestant, (b) an expectorant and (c) an antitussive. ~ -l~ BACKGROUND OF THE INVENTION
The common col~d, although not usually a serious illness, is a highly prevalent, discomforting and annoying infliction. The ter0 ~common cold~ is applied to minor respiratory illnesses caused by a variety of different respiratory viruses. ~hile rhinoviruses are the ma~or known cause of common colds, accounting for approximately 30 percent of colds in adults, viruses in several other groups are also important. ~hile immune responses occur, and infection with some respiratory tract viruses therefore could be prevented by a vaccine, development of a polytypic vaccine to cover all possible agents is impractical. Thus, the problem of controlling acute upper respiratory disease presents complex challenges, and the long-desired discovery of a single cure for the common cold is an unreallstic expectation.
Early symptoms may be minimal w~th only mild malaise, sore throat and nasal complaints. With rhinovirus infection9 symptoms of nasal ~o discharge, nasal congestion, and sneezing usually commence on the first day of illness and progress to maximum severity by the second or third day. Along with nasal symptoms may come sore, dry or scratchy throat and hoarseness and cough. Other symptoms may include mild burning of the eyes, loss of smell and taste, a feeling of pressure or fullness in the sinuses or ears, headache, and vocal impairment.
Fever can occur, but is uncommon. Influenza infection generally includes fever, often of sudden onset and persisting for several days, -WO 9~/14476 PCT/US93/12022 ?.,~S~9~ -2-and with great severity; generalized aches and pains; fatigue and weakness; and chest discomfort.
At present, only symptomatic treatment is available for the common cold. The costs of treating colds with over-the-counter S medications in the United States is estimated at an annual cost of over 1.5 billion dollars. The direct costs of treatment in outpatient clinics is estimated at almost four billion dollars. Indirect costs, based on the amount of loss in wages because of restricted activity are substantially higher.
Exemplary prior art formulations for treatment of cough, cold, cold-llke and/or flu symptoms and the discomfort, pain, fever and general malaise assoc~ated therewith generally contain an analgesic (aspir~n or acetaminophen) and one or more antihistaminics, decon-gestants, cough suppressants, antitussives and expectorants.
The use of non-steroidal anti-inflammatory drugs to combat inflammation and attendant pain is accepted medical practice. The non-steroidals are commonly employed to rel~eve pain and ~nflammation associated with, for example, burs1tis, arthritis, headache and the like. Among the most commonly used drugs of the non-narcotic anal-gesic class of drugs are asptr~n, acetaminophen, ibuprofen and naprox-en. Aspirin, acetaminophen and ibuprofen have heretofore been includ-ed as the pain rel~ever and fever-reducing component in conventional cough/cold multi-symptom alleviating compositions. These commercially marketed products generally cont~in in addition to aspirin, acetamino-phen or ibuprofen, one or more antihistaminics, decongestants, cough-suppressants, antitussives and expectorants.
Ibuprofen, or ( ) 2-(p-isobutylphenyl)propionic acid, is well-known as a nonsteroidal anti-inflammatory drug having analgesic and antipyretic activity. Ibuprofen {s currently marketed by prescription in the Uni~ed States generically, as well as under tradenames such as Motrin~, which is available in 400, 600 and 800 mg tablets for oral administration. Ibuprofen has recently also become avail~ble in this country in non-prescription strength (200 ~g) under a variety of tradenames, including Advil- and Nuprin, as well as in generic form. For the treatment of mild to moderate pain, ~00 mg every 4 to 6 hours, not to exceed 3200 mg daily, is generally recommended for Motrin. The lower dose over-the-counter products are generally recommended for minor aches and pains, to be used orally at .~ WO 94/14476 21 5 1 9 1 2 PCT/US93/12022 ' the 200 to 400 mg level, eYery 4 to 6 hours, not to exceed 1200 mg daily unless directed by a physician.
Flurbiprofen, or (+) [1,1'-biphenyl~-4-acetic acid, 2-fluoro-alphamethyl, is also well-known as a nonsteroidal S anti-inflammatory drug having analgesic and antipyretic activity.
Flurbiprofen is currently marketed by prescription in the United States under the tradename Ansaid~, which is available in 50 and 100 mg tablets for oral admin~stration.
Ketoprofen, or (+) 2-(3-benzoylphenyl)propionic acid, another well-known nonsteroidal anti-inflammatory drug having analgesic and antipyret~c activity is currently marketed by prescription in the United States under the tradename Orudis , which is available in 25, 50 and 75 mg capsules for oral administration. For the treatment of mild to moderate pain, 25-50 mg every 6 to 8 hours, not to exceed 300 mg taily, is generally recommended for Orudis . ~ee Phys7c~tn's Desk Reference, 46th edi-tion, 1992, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, N.J. 07649, pp. 2351-54, 2319-20 and 2488-90, the disclosure of which ~s incorporated herein.
As apparent from their chemical nomenclature, these analgesic agents are racemic mixtures. It is only the racemic mixture of these agents which have in fact ever been marketed. There have, however, been some studies of the individual S(+) and R(-) enantiomer of ibuprofen. In the body, some of the R(-) enantiomer is converted to the S(~) enantiomer, which is the pharmaceutically active form of ibuprofen.
The use of the racemic mixture of ibuprofen together with caffeine has been disclosed in, for example, in U.S. Patent 4,464,376 to Sunshine et al. issued August, 7, 1984. The use of ibuprofen, as well as other of the newer non-steroidal anti-inflammatory agents (i.e., excluding aspirin, acetaminophen and phenacetin) in the preparation of cough/cold pharmaceutical compositions containing amines, has been disclosed in, for example, U.S.
Patent 4,552,899 to Sunshine et al. issued November 12, 1985.
The use of naproxen as well as other of the newer non-steroidal anti-inflammatory agents (i.e., excluding aspirin, acetaminophen and phenacetin) in the preparation of cough/cold ph~rmaceutical composi-tions has been disclosed in, for example, U.S. Patent 4,552,899 to Sunshine et al. issued November 12, 1985. The use of some of these WO 94/14476 PCT/US93/12022 ~ -2~S~ 91?~ _4_ newer NSAID's alone to treat upper respiratory infections has been disclosed in ~Therapeutic Utility of Naproxen in Acute Upper Respira-tory Infection -- Multiclinical Double Blind Study~ Kansenshocaku Zasshi 52 (5):148-163 (1978), ~Clinical Evaluation of Sulindac (Clino-ril) in the Treatment of Acute Upper Respiratory Tract Inflammation-- Double Blind Comparison ~ith Ibuprofen~, Kansenshoqaku Zasshi, Vol.
57, No. 3, pp. 260-272 (1983); ~Double Blind Controlled Study of Miroprofen tn Acute Upper Respiratory Tract Infections. Comparison with Ibuprofen~ Kansenshoqaku Zasshi, Vol. 50, Ho. 5, pp. 435-453, 1982, ~Therapeutic Effects of Fenbufen on the Common Cold. Multi-clinic Double-Blind Study~ Kansenshoqaku Zasshi, Vol. 51, No. 4, pp.
184-196, (1977); ~Cl~nical Evaluation of Clinoril Tablets in Acute Respiratory Tract Infections~, Kansenshoqaku Zasshi, Vol. 56, No. 12, pp. 1186-1195, 1982.
The use of the S(+) form of 1buprofen has been disclosed in, for example, U.S. Patent ~,851,444 to Sunshine et ~l. issued July 25, 1989 and in combination with antihistamines in WO 9,205,783 to Gates et al.
published April 16, ~992.
The present ~nventors have found that selected compositions comprising an analgesic agent substantially free of its R(-) ant~pode selected from the group consisting of (S+)-ibuprofen, (S+) flurbiprofen and (Sl) ketoprofen, pharmaceutically-acceptable salts thereof and mixtures thereof, wlth at least one of (a) a decongestant, (b) an expectorant and (c) an antitussive prov~des improved treatment, management or mitigation of cold, cold-llke and/or flu symptoms.
It is therefore ~n ob~ect of the present invention to provide a method for the treatment of cough, cold, cold-lik~ and/or flu symptoms in a mammalian organism in need of such treatment comprising adminis-tering to such organism the compositions of the present invention.
Such symptoms as used herein refer to coryza, nasal congestion, sinus congestion, sinus pain, upper respiratory infections, allergic rhinitis, otitis, sinitis, etc.
SUMMARY OF THE INVENTION
The present invention relates to compositions and methods for providlng improved treatment, management or mitigation of cold, cold-like and/or flu symptoms by administering a safe and effective amount of a composition comprising an analgesic agent substantially free or of its R(-) antipode selected from the group cons~sting of ` WO 94/14476 2151912 PCT/US93/12022 .

(S+)-ibuprofen, (S+) flurbiprofen and (S+) ketoprofen, pharmaceutically-acceptable salts thereof, and mixtures thereof along w~th at least one of (a) a decongestant, (b) an expectorant and (c) an antitussive.
All percentages and ratios used herein are by weight unless otherwise indicated.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compositions and methods for providing improved treatment, management or mitigation of cold, cold-like and/or flu symptoms by admin~ster~ng a s~fe and effective amount of a composition compris~ng an analgesic agent substantially free or of its R(-) antipode selected from the group consisting of (S+)-ibuprofen, (S+) flurbiprofen and (S+) ketoprofen, pharmaceutically-acceptable salts thereof, and mixtures thereof along with at least one of (a) a decongestant, (b) an expectorant and (c) an antitussive.
The term ~S(+)~ as applied to the analgesic agents herein is intended to encompass not only the dextrorotatory or S(+) isomer of these agents but ~lso any pharmaceutically acceptable, analgesically effect~ve s~lt thereof. The express~on ~substantially free of the R(-) antipode~ as used in con~unction with the term ~S(+)~ means that the S(+) enantiomer is suffic~ently free ~t ~s R(-) antipode to exert the desired onset-hastened and enhanced analgesic effect. Practically speaking, th~s means that the active ingredient should contain at least 90X 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 % by weight free of R(-) enantiomer, 1.e., the weight rat~o of S to R ls approximately equal to or greater than 99:1.
The safe and effective amount of S(+) ibuprofen used in the compositions of the present invention generally ranges from about SO
to about 800 mg, preferably from about 50 to about 400 mg, more preferably from about SO to about 200 mg and most preferably from about 50 to about 100 ~9. The safe and effect~ve amount of S(+) 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 WO 9~ 476 PCT/US93/12022 .
9~2 -6-100 mg and most preferably from about 12.5 to about 50 mg. The safe and effective amount of S(+) ketoprofen used in the compos~tions of the present invention generally ranges from about 5 to about 100 mg, preferably from about 5 to about 75 mg, more preferably from about 5 to about 50 mg and most preferably from about 5 to about 25 mg.
The tenm phanmaceut kally acceptable salts~ refers to salts prepared from pharmaceut~cally acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from nonorganic bases include sodium, potassium, llthlum, ammonia, calcium, magnesium, ferrous, zinc,-~anganous, aluminum, ferric, manganic salts and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, tertiary and quater-nary amines, subst~tuted amines ~ncluding naturally occurring substi-tuted amines, cyclic am~nes ~nd basic ion exchange resins, such as lS triethylamine, tr~propylamine, 2-dimethylaminoethanol, 2-diethylaminoeth~nol, lysine, arginine, h~stidine, caffeine, procaine, N-ethylpiperldine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobromine, pur~nes, piperaz~ne, piperid~ne, polyamine res1ns and the l~ke.
The compos~tions of the present ~nvention also ~nclude at least one other pharmacological act~ve selected from the follow~ng class:
(a) a decongestant, (b) an expectorant and (c) an antituss~ve. The decongestants useful in the compositions of the present invention include psEudoephedrine, phenylpropanolamine, phenylephrine and ephe-drine, their pharmaceut~cally acceptable salts, and mixtures thereof.
The antituss~ves useful in the present invention ~nclude those such as dextromethorphan, chlophedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hyd,ocodo~e, hydromorphone, fominoben, their pharmaceutically-acceptable salts, and mixtures thereof. The expectorants (also known as mucolyt~c agents) useful in the present invention include glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their pharmaceutically acceptable salts, and mixtures thereof. All of these components, as ~ell as their acceptable dosage ranges are described in the following: U.S. Patent 4,783,465 to Sunshine et al., issued November 8, 1988, U.S. Patent 4,619,934 to Sunshine et alO~ issued October 28, 1986, which are incorporated by reference herein.

WO 94/14~76 2151912 PCT/US93/12022 Preferably, the pharmaceutical compositions of the present invention comprise the S(+) enantiomer and other pharmacological active in a ratio of S(~) enantiomer: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, granules, lozenges and bulk powders and liquid forms such as syrups and suspensions. These oral forms 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 preferably from about 10% to about 95%, and most preferably from about 25% to about 95% of the active component.
Liquid oral dosage forms preferably contain from about 1% to about 50%
and more preferably from about lX to about 25% and most preferably from about 3% to about 10X of the active component.
Tablets can be compressed, triturated, enteric-coated, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives and flow-inducing agents. Also useful are soft gelatin capsules.
Liquid oral dos~ge forms include aqueous and nonaqueous solu-tions, emulsions, pseudo emulsions, suspensions, and solutions ant/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, taste-masking agents, coloring agents, and flavoring agents. Specific examples of pharmaceutically accept-able carriers and excipients that may be used to formulate oral dosage forms, are described in U.S. Patent 3,903,297, Robert, issued Sep-tember 2, 1975, incorporated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Marshall, ~Solid Oral Dosage Forms,~ Modern Phanmaceutics, Vol. 7, (Banker and Rhodes, editors), 359-427 (1979), incorporated by refer-ence herein. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are described in Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (1980), incorporated herein by reference.
In preparing the liquld oral dosage forms, the active component is incorporated into an aqueous-based orally acceptable pharmaceutical .

~ carrier consistent with conventional pharmaceutical practices. An ~aqueous-based orally acceptable pharmaceutical carrier" is one wherein the entire or predominant solvent content is water. Typical carriers include simple aqueous solutions, syrups, dispersions and suspensions, and aqueous based emulsions such as the oil-in-water type. The most preferred carrier is a suspension of the pharmaceuti-cal composition in an aqueous vehicle containing a suitable suspending agent. Suitable suspending agents include Avlcel RC-591 (a microcrys-talline cellulose/sodium carboxymethyl cellulose mixture available from FMC), guar gum and the llke. Such suspending agents are well known to those skilled in the art. ~hile the amount of water in the compositions of this invention can vary over quite a wide range depending upon the total weight and volume of the active component and other optional non-active ingredients, the total water content, based on the weight of the final composit~on, will generally range from about 20 to about 7S%, and, preferably, from about 20 to about 40%, by weight/volume.
Although water itself may make up the entire carrier, typical liquid formulations preferably contain a co-solvent, for example, 2C propylene glycol, glycerin, sorbitol solut~on and the like, to assist solubilization and incorporatlon of water-insoluble ingredients, such as flavoring oils and the like into the composit~on. In general, therefore, the compositions of this invention preferably contain from about S to about 25 volume/volume percent and, most preferably, from about 10 to about 20 volume/ volume percent, of the co-solvent.
~ he compositions of this invention ~-y optionally contain one or more other known therapeutic agents, particularly those commonly utilized 1n cough/cold preparations, such as, for example, an antihistamine such as chlorphen~ramine, brompheniramine, dexchlorphen-iramine, dexbromphreniramine, triprolldine, azatadine, doxylamine,tripelennamine, cyproheptadine, hydroxyzine, clemastine, carbinox-amine, phenindamine, bromodiphenhydramine, pyrilamine, the1r pharmaceutically acceptable salts, as well as the non-sedating anti-histamines which inclute acrivastine, AHR-11325, astemizole, azelas-tine, cet~rizine, ebastine, ketotifen, lodoxamide, loratidine, levoca-bastine, mequitazine, oxatomide, setastine, tazifyll~ne, temelastine, and terfenatine, their pharmaceutically acceptable salts: all of these components, as well as their acceptable dosage ranges are g described in the following: U.S. Patent 4,783,465 to Sunshine et al., issued November 8, 1988, U.S. Patent 4,619,934 to Sunshine et al., issued October 28, 1986, which are incorporated by reference herein.
Also useful are bronchodilators such as terbutaline, aminophylline, S epinephrine, isoprenaline, metaproterenol, bitoterol, theophylline and albuterol as well as other analgesic agents such as acetaminophen and aspirin. A highly preferred optional component is caffeine.
Other optional ingredients well known to the phan~acist's art may also be included in amounts generally known for these ingredients, for example, natural or artificial sweeteners, flavoring agents, colorants and the like to provide a palatable and pleasant looking final prod-uct, antioxidants, for example, butylated hydroxy anisole or butylated hydroxy toluene, and preservatives, for example, ~ethyl or propyl paraben or sodium benzoate, to prolong and enhance shelf life.
lS METHOD OF T~F~TMENT
The amount of the pharmaceutical composition administered depends upon the percent of actlve ingredients within its formula, which is a function of the amount of the naphthalene derivative and any optional components such as a decongestant, cough suppressant, expectorant and/or antihistamlne required per dose, stability, release character-istics and other pharmaceutical parameters.
Usually from about 1 ~g/kg to about SO mg/kg per day, preferably from about 2 mg/kg to bout 30 mg/kg per day and most preferably from about 3 mg/kg per day to about 20 mg/kg per day of the pharmaceutical composition is administered as described herein. This amount can be given in a single dose, or, preferably, in multiple (two to six) doses repeatedly or sustained release dosages over the course of treatment.
Generally, each individual dosage of the pharmaceutical compositions of the present invention range from about 1 mg/kg to about 25 mg/kg, preferably from about 2 mg/kg to about 15 mg/kg and most preferably from about 3 mg/kg to about 10 mg/kg. While dosages higher than the foregoing are effective to provide relief from cough, cold-like, flu and flu-like symptoms, care must be taken, as with any drug, in some individuals to prevent adverse side effects.
3s The following examples illustrate embodiments of the subject invention wherein both essential and optional ~ngredients are com-bined.

.
$~ 9~2 - lo-EXAMPLE I
A hard gelatin capsule composition for oral administration is prepared by combining the following ingredients:
Inqredient Amount S(+) Ibuprofen 100 mg Pseudoephedrine HCl 30 mg Tritur~te active ingredients and q.s. w~th lactose to selected capsule stze.
Administration of 1 or 2 of the above capsules to a human in need of treatment provides ~mproved relief from cough, cold-l~ke, flu and flu-llke symptoms.
EXAMPLE II
A hard gelatin capsule composition for oral administratlon is prepared by combin~ng the followlng ingredients: ~
Inaredient Amount S(+) Flurbiprofen 50 ~q Pseudoephedrine HCl 30 mg Astemizole 5 ~q Glyceryl gualacolate 100 mg Triturate active ingredients and q.s. with lactose to selected capsule size.
Administr~tion of 1 or 2 of the above capsules to a human in need of treatment provides improved relief from cough, cold-like, flu and flu-like symptoms.
EXAMPLE III
A llqu~t composltion for oral administration is prepared by combining the following inqredients:
Inqredlent X W/V
S(+) Ibuprofen 1.00 Alcohol (95%) 25.000 Pseudoephedrine HCl 0.30 Propylene Glycol 25.000 Sodium Citrate 2.000 Citric Acid 0.250 Liquid Sugar (Simple Syrup) 25.00 61ycerin 7.000 Colorants 0.008 Flavor 0-500 ~ater, Purified QS 100.000 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, and actives other than ibuprofen are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then colorants added. In a separate container the colorants are added to purified water (approximately 0.5% of the final batch volume). This colorant solution is then added to the first batch container. In a seperate container the 1buprofen is added to the alcohol wh~le stirring. The propylene glycol, other actives 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 st~rred.
'Administration of 10 01 to 20 ml (2 to ~ teaspoonsful) to a human in need of treatment provides improYed rel1ef from cough, cold-like, flu and flu-like symptoms.
EXAMPLE IV
A l~quid composition for oral administration is prepared by combining the following ingredients:
Inqred~ent X ~/V
S(~) Ibuprofen 1.00 Chlorpheniramine Maleate 0.02 Pseudoephedrine HCl 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 ~ater, Purified QS 100.00 The purified water (approximately lOX of the final batch volume) is poured into a batch container equipped with a lightnin' mixer. The sodium citrate, citric acid, pseudoephedrine HCl and chlorpheniramine maleate ~re added sequentially and dissolved with agitation. The ?,~.S~9~ - 12- -glycerin and liquid sugar are then added. In a seperate container the colorants are added to pur~fied water (approximately 0.5% of the final batch volume). This colorant solutlon is then added to the first batch container. In a separate container the lbuprofen is added to the alcohol while stirring. ~he 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.
Administratlon of 10 ml to 20 ml (2 to ~ Teaspoonsful) to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect.
EXAMPLE V
A liquid composition for oral admin~stratlon is prepared ~y combining the following ingred~ents:
Ingred~ent X ~/Y
S(+) Ibuprofen 1.00 Pseudoephed.ine HCl 0.30 Chlorphen~ramine Maleate 0.02 Dextromethorphan HBr 0.15 Alcohol (95X) 25.00 Propylene Glycol 25.00 Sodium Citr~te 2.00 Citric Acid 0.25 Liquid Sugar (Simple Syrup) 25.00 Glycerin 7.00 Colon~nts 0.008 Flavor 0.50 ~ater Purified QS 100.00 The pur1f~ed water (approximately 10% of the final batch volume) is poured into a batch container equipped with a l~ghtnin mixer. The sodium citrate citric acid pseudoephedrine HCl and chlorpheniramlne maleate are added sequentially and d~ssolved with agitation. The glycer~n and liqu~d sugar are then added. In a seperate container the 3s color~nts are added to purified water (approximately O.5X of the final batch volume). This colorant solution is then added to the first batch container. In a separate container the ibuprofen and dextro-methorphan HBr are added sequentially to the alcohol while stirring.

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 teaspoonsful) to a human in need of treatment provides improved relief from cough, cold-like, flu and flu-like symptoms.

Claims (8)

1. A composition 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 an analgesic agent substantially free or of its R(-) antipode selected from the group consisting of (S+)-ibuprofen, (S+) flurbiprofen and (S+) ketoprofen, pharmaceutically-acceptable salts thereof, and mixtures thereof along with at least one of (a) a decongestant, (b) an expectorant and (c) an antitussive.

2. A pharmaceutical composition according to Claim 1 comprising from 50 to 800 mg, preferably 50 to 400 mg and most preferably 50 to 200 mg S(+)-ibuprofen.

3. A pharmaceutical composition according to Claim 1 comprising from 12.5 to 300 mg, preferably from 12.5 to 100 mg and most preferably from 12.5 to 50-mg S(+)-flurbiprofen.

4. A pharmaceutical composition according to Claim 1 comprising from 5 to 75 mg, preferably from 5 to 50 mg and most preferably from 5 to 25 mg S(+)-ketoprofen.

5. A pharmaceutical composition according to any of the preceding Claims wherein said decongestant is pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, mixtures thereof or pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition according to any of the preceding 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.

7. A pharmaceutical composition according to any of the preceding 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.

8. A composition according to any of the preceding Claims which further comprises an antihistamine which is selected from the group consisting of chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbrompheniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, pyrilamine, acrivastine, AHR-11325, phenindamine, actemizole, azatadine, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, mixtures thereof or pharmaceutically acceplable salts thereof.