TECHNICAL FIELD

The present invention relates to novel methods of using certain napthalene derivatives, preferably certain 2-(6'-substituted-2'-naph- thyl)-acetic acid derivatives and salts and esters thereof in the treatment, management or mitigation of cold, cold-like and/or flu symptoms.

BACKGROUND OF THE INVENTION

The common cold, although not usually a serious illness, is a highly prevalent, discomforting and annoying infliction. The term "common cold" is applied to minor respiratory illnesses caused by a variety of different respiratory viruses. While rhinoviruses are the major known cat_..a of common colds, accounting for approximately 30

15 percent of colds in adults, viruses in several other groups are also important. While 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

20 a single cure for the common cold is an unrealistic expectation.

Early symptoms may be minimal with only mild malaise, sore throat and nasal complaints. With rhinovirus infection, symptoms of nasal discharge, nasal congestion, and sneezing usually commence on the first day of illness and progress to maximum severity by the second or

25 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

30 includes fever, often of sudden onset and persisting for several days, and with great severity; generalized aches and pains; fatigue and weakness; and chest discomfort. rt present, only symptomatic treatment is available for the common cold. The costs of treating colds with over-the-counter 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-like and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith generally contain an analgesic

(aspirin 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 relieve pain and inflammation associated with, for example, bursitis, arthritis, headache and the like. Among the most commonly used drugs of the non-narcotic anal¬ gesic class of drugs are aspirin, acetaminophen, ibuprofen and naprox¬ en. Aspirin, acetaminophen and ibuprofen have heretofore been includ¬ ed as the pain reliever and fever-reducing component in conventional cough/cold multi-symptom alleviating compositions. These commercially marketed products generally contain in addition to aspirin, acetamino¬ phen or ibuprofen, one or more antihistaminics, decongestants, cough- suppressants, antitussives and expectorants. Naproxen ((+)-2-(6 methoxy-2-naphthyl) propionic acid), a non- steroidal anti-inflammatory drug (NSAID), became available in the U.S. for the treatment of rheumatoid arthritis in 1976. Naproxen has been further indicated for osteoarthritis, tendonitis and bursitis, anky- losing spondylitis and acute gout. Additional indications include mild to moderate pain and primary dysmenorrhea. Naproxen has also been demonstrated to have less severe gastrointestinal and central nervous system adverse effects than aspirin.

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 pharmaceutical 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 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" Kansenshoqaku Zasshi 52 (5):148-163 (1978), "Clinical Evaluation of Sulindac (Clino- ril ^® ) in the Treatment of Acute Upper Respiratory Tract Inflammation

-- Double Blind Comparison With Ibuprofen", Kansenshoαaku Zasshi, Vol. 57, No. 3, pp. 260-272 (1983); "Double Blind Controlled Study of Miroprofen in Acute Upper Respiratory Tract Infections. Comparison with Ibuprofen" Kansenshoαaku Zasshi. Vol. 50, No. 5, pp. 435-453, 1982, "Therapeutic Effects of Fenbufen on the Common Cold. Multi- clinic Double-Blind Study" Kansenshogaku Zasshi, Vol. 51, No. 4, pp. 184-196, (1977); "Clinical Evaluation of Clinoril Tablets in Acute Respiratory Tract Infections", Kansenshogaku Zasshi. Vol. 56, No. 12, pp. 1186-1195, 1982. As described above, early symptoms of respiratory illnesses may be minimal and hence left untreated until they become much more _severe . i has been found, however, that administration of naproxen within the first 36 hours, preferably within the first 24 hours, and most preferably within the first 12 hours of the discovery of the onset of cough, cold, cold-like and/or flu symptoms by the sufferer provides significantly improved symptomatic relief from these symp¬ toms.

It is therefore an object of the present invention to provide a method for the treatment of cough, cold, cold-like and/or flu symptoms in a mammalian organism in need of such treatment comprising adminis¬ tering to such organism a symptom-relieving, analgesically and anti- inflammatorily effective amount of naproxen within the first 35 hours of the discovery of the onset of said symptoms by said organism, that is, generally within about 36 hours after viral infection, or innocu- lation . Such symptoms as used herein refer to coryza, nasal conges¬ tion, upper respiratory infections, allergic rhinitis, otitis, sini- tis, etc.

It is a further object of this invention to provide methods of treating such symptoms by administration of naproxen in combination with at least one or more of an antihistamine, decongestant, cough suppressant, antitussive and/or expectorant within the first 36 hours of the discovery of the onset of these symptoms.

SUMMARY OF THE INVENTION The present invention relates to a method for eliciting an enhanced response in the treatment of cough ^' , cold, cold-like and/or flu symptoms in a human or lower animal in need of such treatment, comprising administering to such mammaliam organism in need of such

treatment a symptom relieving, analgesically and anti-inflammatorily effective amount of a specific naphthalene derivative within the first 24 hours of the discovery of the onset of symptoms.

All percentages and ratios used herein are by weight unless otherwise indicated.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods for the treatment of cold, cold-like, flu and flu-like symptoms by administration of a safe and effective amount of a napthalene derivative, preferably a 2-(6'- substituted-2'-naphthyl)-acetic acid derivative, and salts and esters thereof. These compositions are administered to a mammalian organism for the treatment of cough, cold, cold-like and/or flu symptoms within the first 36 hours of the discovery of the onset of said symptoms.

The compounds of this invention are the carboxylic acids and carboxylic acid esters represented by the following formula, and the pharmaceutically acceptable salts of the carboxylic acids represented by the following formula:

In the above formula,

R ¹ is alkyl having up to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, alkoxy ethyl having up to 7 carbon atoms, tri- f1uoromethyl , vinyl, ethynyl , halo (iodo, bromo, chloro or fluoro) alkoxy having up to 6 carbon atoms, difluoromethoxy, al oxymethoxy having up to 7 carbon atoms, alkylthiomethyloxy having up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, alkoxymethylthio having up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkylsub- stituted phenyl having up to 8 carbon atoms; one of R ² and R ³ is hydrogen, the other being methyl, ethyl or difluoromethyl or R ² or R ³ together are methylene;

R* is hydrogen, alkyl having up to 22 carbon atoms, unsaturated alkyl having up to 22 carbon atoms, cycloalkyl having from 3 to 7

carbon atoms, cycloalkylmethyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 9 carbon atoms, 2-cycloalkylethyl having from 5 to 10 carbon atoms, 3-cyclopentylethyl having from 5 to 10 carbon atoms, 3-cyclopentylpropyl , 3-cyclohexylpropyl , benzyl, 2-phenylethyl or 3-phenylpropyl .

Preferably, the 6'-substituent (represented by R ¹ in the above formula) is methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl , vinyl, ethynyl , fluoro, chloro, methoxy, ethoxy, methoxy ethyloxy, difluoromethoxy, methylthio, ethylthio, methoxy ethylthio, difluoro- methylthio or phenyl; one of R ² and R ³ is hydrogen and the other is methyl; and R ⁴ is hydrogen, methyl, ethyl, propyl , isopropyl, butyl, pentyl , isopentyl, hexyl , 2-hexyl, isohexyl, heptyl , isoheptyl, octyl , isooctyl, nonyl , isononyl, decyl , isodecyl, undecyl , dodecyl , tri- decyl , tetradecyl , pentadecyl , hexadecyl , cyclopentyl or cyclohexyl. The term "alkyl" refers to and includes branched or straight chain hydrocarbons. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tertiary-butyl, neopentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl , tridecyl, isotetradecyl , pentadecyl, isohexadecyl , heptadecyl , eicosyl, docosyl , and the like. The term "unsaturated alkyl" refers to unsaturated hydrocarbon groups such as vinyl, allyl, propenyl , crotyl , isopropenyl, 2-propynyl, 1-propenyl, 2-butenyl, 1,3-butadienyl , 2-pentenyl, 2-penten-4-ynyl and the like.

The term "cycloalkyl" refers to cyclo hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term 'alkoxy" refers to straight or branched chain alkyl ether groups such as methoxy, ethoxy, 2-propoxy, butoxy, 3-pentoxy and the like.

The term "al oxymethyloxy" refers to methyl ether groups substi- tuted with one alkoxy group (defined above) such as methoxymethyloxy, e .oxymethloxy, isopropoxymethyloxy and the like.

The term "alkylthio" refers to straight or branched chain alkyl- thio ether groups such an methylthio, ethylthio, propylthio. 2-propyl- thio, 2-butylthio, pentylthio, 3-hexylthio and the like. The term "alkylthio ethyloxy" refers to methyl ether groups substituted with an alkylthio group (defined above) such as methyl- thiomethyloxy, 2-propylthiomethyloxy, pentylthiomethloxy and the like.

The term "al ylthio ethylthio" as used herein denoted methylthio ether groups substituted with an alkylthio group such as methylthio- methylthio, ethylthiomethylthio and the like.

The term "alkoxymethylthio" refers to methylthio ether groups substituted with an alkoxy group such as methocymethylthio, ethoxy- ethylthio, 2-propoxymethylthio and the like.

The term "aryl" refers to phenyl, or o-, m- and/or p- alkylsub¬ stituted phenyl derivatives such as phenyl, otolyl, m-tolyl, p-tolyl, o-ethylphenyl , m-ethylphenyl, p-ethylphenyl, xylyl and the like. The term "cycloalkylmethyl" refers to cycloalkyl substituted methyl groups such as cyclopropylmethyl , cyclobutylmethy, cyclopentyl- methy, cyclohexylmethyl , cycloheptylmethyl , and the like. The term "2-cycloalkylethyl" refers to an ethyl group substituted at the 2-position with a cycloalkyl group such as 2-cyclopropylethyl, 2-cy- clobutylethyl , 2-cyclopentylethyl , 2-cyclohexylethyl and 2-cyclo- heptylethyl .

The most preferred compound used herein is (+)-2-(6'-methoxy- 2-napthyl) propionic acid, and salts and esters thereof.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from nonorganic bases include sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc, manganous, 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, substituted amines including naturally occurring substi¬ tuted amines, cyclic amines and basic ion exchange resins, such as triethylamine, tripropylamine, 2-dimethylaminoethanol , 2-diethylamino- ethanol, lysine, argim ^' ne, histidine, caffeine, procaine, N-ethylpip- eridine, hydrabamine, choline, betaine, ethyleneciamine, glucosamine, methylglycamine, theobromine, purines, piperazine, piperidine, poly- amine resins and the like.

When one of R ² and R ³ is hydrogen and the other is methyl or difluoromethyl , the compounds of Formula 1 exist as pairs of enantio- morphs or optical isomers. Each enantiomorph- and mixtures thereof are included within the present invention. The compounds of Formula 1 which exist as pairs of enantiomorphs can be administered as racemic

mixtures or they can be administered as resolved enantiomorphs. In some instances, one enantiomorph exhibits greater anti-inflammatory, analgesic and/or anti-pyretic activity than the other corresponding enantiomorph. The most preferred derivatives for use herein are the S(+)enantiomorphs.

The optical isomers can be resolved by conventional means, such as selective biological degradation or by the preparation of dias- tereo-isomeric salts of the naphthalene derivative with an optically active amine base such cinchonidine and separating the diastereoiso- mers by fractional crystallization. The separated diastereoisomeric salts are then acid cleaved to yield the respective optical isomer.

These compounds are fully disclosed in U.S. Patent 3,904,682 to Fried et al . issued September 9, 1975 and in U.S. Patent 3,998,966 to Fried et al . issued December 21, 1976, both incorporated by reference herein, as having anti-inflammatory, analgesic and anti-pyretic activities and as being useful in the treatment and elimination of inflammation, such as rheumatism, concussion, laceration, arthritis, bone fractures, post-traumatic conditions, and gout.

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 1% to about 25% and most preferably from about 3% to about 10% 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 dosage forms include aqueous and nonaqueous solu- tions, emulsions, pseudo emulsions, suspensions, and solutions and/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending

agents, diluents, sweeteners, coloring agents, and flavoring agents. Specific examples of pharmaceutically acceptable carriers and exci- pients that may be used to formulate oral dosage forms, are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975, incorpor- ated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics. Vol. 7. (Banker and Rhodes, editors), 359-427 (1979), incorporated by reference herein. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are described in Remington's Pharma¬ ceutical Sciences (Arthur Osol , editor), 1553-1593 (1980), incorpora¬ ted herein by reference.

In preparing the liquid 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 Avicel RC-591 (a microcrys- talline cellulose/sodium carboxymethyl cellulose mixture available from FMC), guar gum and the like. Such sus ending agents are well known to those skilled in the art. While the amount of water in the compositions of this invention can vary over quite a wide range depending upon the 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 composition, will generally range from about 20 to about 75%, 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, propylene glycol, glycerin, sorbitol solution and the like, to assist solubilization and incorporation of water-insoluble ingredients, such as flavoring oils and the like into the composition. In general, therefore, the compositions of this invention preferably contain from

about 5 to about 25 volume/volume percent and, most preferably, from about 10 to about 20 volume/ volume percent, of the co-solvent.

The compositions of this invention may optionally contain one or more other known therapeutic agents, particularly those commonly utilized in cough/cold preparations, such as, for example, a decon¬ gestant such as pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, their pharmaceutically acceptable salts; an antitussive such as dextromethorphan, chlophedianol , carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fo inoben, their phar aceutically-acceptable salts; an expectorant or mucolytic such as glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol , their pharmaceu¬ tically acceptable salts; and an antihistamine such as chlorphenir- a ine, brompheniramine, dexchlorphenira ine, dexbromphreniramine, triprolidine, azatadine, doxylamine, tripelennamine, cyproheptadine, hydroxyz.ne, cle astine, carbinoxamine, phenindamine, bromodiphenhy- dramine, pyrilamine, their pharmaceutically acceptable salts, as well as the non-sedating antihistamines which include acrivastine, AHR- 11325, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodox- amide, loratidine, levocabastine, equitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, their pharmaceutically acceptable salts: all of these components, as well as their accept¬ able 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 al . , issued October 28, 1986, which are incorporated by reference herein. Also useful are bronchodilators such as terbutaline, aminophylline, epinephrine, isoprenaline, meta- proterenol, bitoterol, theophylline and albuterol. A highly preferred optional component is caffeine, which is preferably present at a level of from about 10% to about 50%.

Other optional ingredients well known to the pharmacist's art may also be included in amounts generally known for these ingredients, for e. iple, 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, methyl or propyl paraben or sodium benzoate, to prolong and enhance shelf life.

METHOD OF TREATMENT The amount of the pharmaceutical composition administered depends upon the percent of active 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 antihistamine required per dose, stability, release character¬ istics and other pharmaceutical parameters.

Usually from about 1 mg/kg to about 50 mg/kg per day, preferably from about 2 mg/kg to about 30 mg/kg per day and most preferably from about 3 mg/kg per day to about 20 mg/kg per 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. Typical unit dosage forms for oral administration generally comprise from about 100 mg to about 2000 mg, preferably from about 150 mg to about 600 mg and most preferably from about 150 mg to about 400 mg of the naphthalene derivative. 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. The composition is administered within about 36 hours preferably about 24 hours, and, most preferably within about 12 hours of discov¬ ery of the onset of symptoms by the individual. The onset of symptoms generally occurs within about 36 hour after viral infection or inno- culation . The following examples illustrate embodiments of the subject invention wherein both essential and optional ingredients are com¬ bined.

EXAMPLE I A soft gelatin capsule composition for oral administration is prepared by combining the following ingredients:

Ingredient Amount Naproxen 200 mg

Pseudoephedrine HC1 30 mg

Triturate active ingredients and q.s. with lactose to weight sufficient to fill selected capsule size.

Administration of two of the above capsules within the first 24 hours of the discovery of the onset of cough, cold, cold-like and/or flu symptoms provides significantly improved symptomatic relief from these symptoms.

EXAMPLE II A soft gelatin capsule composition for oral administration is prepared by combining the following ingredients:

Ingredient Amount

Naproxen 200 mg

Astemizole 10 mg

Pseudoephedrine HC1 30 mg Glyceryl guaiacolate 100 mg

Triturate active ingredients and q.s. with lactose to weight sufficient to fill selected capsule size.

Administration of two of the above capsules within the first 24 hours of the discovery of the onset of cough, cold, cold-like and/or flu symptoms provides significantly improved symptomatic relief from these symptoms.

EXAMPLE III A soft gelatin capsule composition for oral administration is prepared by combining the following ingredients: Ingredient Amount

Naproxen 200 mg

Terfenadine 60 mg

Triturate active ingredients and q.s. with lactose to weight sufficient to fill selected capsule size. Administration of two of the above capsules within the first 24 hours of the discovery of the onset of cough, cold, cold-like and/or flu symptoms provides significantly improved symptomatic relief from these symptoms.

EXAMPLE IV A liquid composition for oral administration is prepared by combining the following ingredients:

Ingredient % W/V Naproxen 6.667

Ethanol (95%) 25.000

Propylene Glycol 25.000

Sodium Citrate 2.000

Citric Acid 0.250 Liquid Sugar 70.000

Glycerin 7.000

Colorants 0.008

Flavor 0.500

Water, 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 and citric acid are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then added. In a seperate container the colorants are added to purified water (approxi- mately 0.5% of the final batch volume). This colorant solution is then added to the first batch container. In a seperate container the naproxen is added to the alcohol while stirring. The propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added ttr the first container. The remaining purified water is added to the resulting mixture and stirred.

Administration of 30 ml within the first 36 hours of the disco¬ very of the onset of cough, cold, cold-like and/or flu symptoms provides significantly improved symptomatic relief from these symp- toms.

EXAMPLE V A liquid composition for oral administration is prepared by combining the following ingredients:

Ingredient % W/V Naproxen 6.667

Pseudoephedrine HC1 0.200

Ethanol (95%) 25.000

Propylene Glycol 25.000

Sodium Citrate 2.000 Citric Acid 0.250

Liquid Sugar 70.000

Glycerin 7.000

Colorants 0.008

Flavor 0.500 Water, 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 pseudoephedrine HC1 are added sequen¬ tially and dissolved with agitation. The glycerin and liquid sugar are then added. In a seperate 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 naproxen is added to the alcohol while stir¬ ring. 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 30 ml within the first 36 hours of the disco¬ very of the onset of cough, cold, cold-like and/or flu symptoms provides significantly improved symptomatic relief from these symp¬ toms.

EXAMPLE VI A liquid composition for oral administration is prepared by combining the following ingredients:

Ingredient % W/V Naproxen 6.667

Pseudoephedrine HC1 0.200

Chlorpheniramine Maleate 0.013

Ethanol (95%) 25.000

Propylene Glycol 25.000 Sodium Citrate 2.000

Citric Acid 0.250

Liquid Sugar 70.000

Glycerin 7.000

Colorants 0.008 Flavor 0.500

Water, 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, pseudoephedrine HC1 and chlorpheniramine maleate are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then added. In a seperate 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 naproxen is added to the alcohol while stirring. The propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homoge¬ neous and then added to the first container. The remaining purified water is added to the resulting mixture and stirred.

Administration of 30 ml within the first 36 hours of the disco- very of the onset of cough, cold, cold-like and/or flu symptoms provides significantly improved symptomatic relief from these symp¬ toms.

EXAMPLE VII A liquid composition for oral administration is prepared by combining the following ingredients:

The purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer. The sodium citrate, citric acid, pseudoephedrine HC1 and chlorpheniramine maleate are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then added. In a seperate 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 naproxen 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 30 ml within the first 36 hours of the disco¬ very of the onset of cough, cold, cold-like and/or flu symptoms provides significantly improved symptomatic relief from these symp¬ toms.

WHAT IS CLAIMED IS: