WO1992004022A1

WO1992004022A1 - Use of compositions containing 2-(6'-substituted-2'-naphthyl)-acetic acid derivatives for the treatment of respiratory disorders

Info

Publication number: WO1992004022A1
Application number: PCT/US1991/006399
Authority: WO
Inventors: James Vincent Sorrentino; Donald Kay Riker
Original assignee: Richardson Vicks Inc.
Priority date: 1990-09-11
Filing date: 1991-09-09
Publication date: 1992-03-19
Also published as: EG19841A; IE913184A1; PT98921A; MX9101031A; MA22278A1; AU8505991A

Abstract

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 mammalian organism in need of such treatment a symptom relieving, analgesically and anti-inflammatorily effective amount of a specific naphthalene derivative within the first 36 hours of the discovery by said human or lower animal of the onset of said symptoms.

Description

Use of compositions containing 2-(6'-substituted-2'-naphthyl)-acetic acid deri vatives for the treatment of respiratory disorders

TECHNICAL FIELD

The present invention relates to novel methods of using certain napthalene derivatives, preferably certain 2-(6'-substituted-2'-naphthyl)-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 cause of common colds, accounting for approximately 30 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 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 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, 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 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, decongestants, 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 analgesic class of drugs are aspirin, acetaminophen, ibuprofen and naproxen. Aspirin, acetaminophen and ibuprofen have heretofore been included 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, acetaminophen or ibuprofen, one or more antihistaminics, decongestants, coughsuppressants, 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, ankylosing 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 compositions 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 Respiratory Infection -- Multiclinical Double Blind Study" Kansenshoqaku Zasshi 52 (5):148-163 (1978), "Clinical Evaluation of Sulindac (Clinoril^®) in the Treatment of Acute Upper Respiratory Tract Inflammation -- Double Blind Comparison With Ibuprofen", Kansenshogaku Zasshi, Vol. 57, No. 3, pp. 260-272 (1983); "Double Blind Controlled Study of Miroprofen in Acute Upper Respiratory Tract Infections. Comparison with Ibuprofen" Kansenshogaku 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. it 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 symptoms.

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 administering 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 innoculation . Such symptoms as used herein refer to coryza, nasal congestion, upper respiratory infections, allergic rhinitis, otitis, sinitis, 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,

R¹ is alkyl having up to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, al koxymethyl having up to 7 carbon atoms, trifluoromethyl, vinyl, ethynyl, halo (iodo, bromo, chloro or fluoro) alkoxy having up to 6 carbon atoms, difluoromethoxy, al koxymethoxy having up to 7 carbon atoms, alkyl thiomethyloxy having up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, alkoxymethylthio having up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkylsubstituted phenyl having up to 8 carbon atoms;

one of R² and R³ is hydrogen, the other being methyl, ethyl or difl uoromethyl or R² or R³ together are methylene;

R⁴ 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 R¹ in the above formula) is methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, ethoxy, methoxymethyloxy, difluoromethoxy, methylthio, ethylthio, methoxymethylthio, difluoro- methylthio or phenyl; one of R² and R³ is hydrogen and the other is methyl; and R⁴ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl, hexyl, 2-hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, dodecyl, tridecyl, 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 "alkoxymethyloxy" refers to methyl ether groups substituted with one alkoxy group (defined above) such as methoxymethyloxy, e hoxymethloxy, isopropoxymethyloxy and the like.

The term "alkylthio" refers to straight or branched chain alkylthio ether groups such an methylthio, ethylthio, propylthio. 2-propylthio, 2-butylthio, pentylthio, 3-hexylthio and the like.

The term "alkylthiomethyloxy" refers to methyl ether groups substituted with an alkylthio group (defined above) such as methylthiomethyloxy, 2-propylthiomethyloxy, pentylthiomethloxy and the like. The term "alkylthiomethylthio" 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, ethoxymethylthio, 2-propoxymethylthio and the like.

The term "aryl" refers to phenyl, or o-, m- and/or p- alkyl substituted 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-cycloalkyl ethyl" refers to an ethyl group substituted at the 2-position with a cycloalkyl group such as 2-cyclopropyl ethyl, 2-cyclobutylethyl, 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 quaternary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as triethyl amine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, argimne, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethyl eneci amine, glucosamine, methylglycamine, theobromine, purines, piperazine, piperidine, polyamine resins and the like.

When one of R² and R³ is hydrogen and the other is methyl or difluoromethyl, the compounds of Formula 1 exist as pairs of enantiomorphs 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 diastereo-isomeric salts of the naphthalene derivative with an optically active amine base such cinchonidine and separating the diastereoisomers 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, sugarcoated, 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 solutions, 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 excipients that may be used to formulate oral dosage forms, are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975, incorporated 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 Pharmaceutical Sciences (Arthur Osol , editor), 1553-1593 (1980), incorporated 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 pharmaceutical 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 suspending agents are well known to those skilled in the art. While the amount of water in the compositions of this invention can vary over quite a wide range depending upon the 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 decongestant such as pseudoephedrine, phenyl propanol amine, phenylephrine and ephedrine, their pharmaceutically acceptable salts; an antitussive such as dextromethorphan, chlophedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, their pharmaceutically-acceptable salts; an expectorant or mucolytic such as glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their pharmaceutically acceptable salts; and an antihistamine such as chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine, azatadine, doxylamine, tripelennamine, cyproheptadine, hydroxyzine, clemastine, carbinoxamine, phenindamine, bromodiphenhydramine, 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, mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, their pharmaceutically acceptable salts: all of these components, as well 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 al., issued October 28, 1986, which are incorporated by reference herein. Also useful are bronchodilators such as terbutaline, aminophylline, epinephrine, isoprenaline, metaproterenol, 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 product, 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 characteristics 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 discovery of the onset of symptoms by the individual. The onset of symptoms generally occurs within about 36 hour after viral infection or innoculation .

The following examples illustrate embodiments of the subject invention wherein both essential and optional ingredients are combined. EXAMPLE I

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

Ingredient Amount

Naproxen 200 mg

Pseudoephedrine HCl 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 I I

Ingredient Amount

Naproxen 200 mg

Astemizole 10 mg

Pseudoephedrine HCl 30 mg

Glyceryl guaiacolate 100 mg

EXAMPLE III

Ingredient Amount

Naproxen 200 mg

Terfenadine 60 mg

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 (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 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 discovery of the onset of cough, cold, cold-like and/or flu symptoms provides significantly improved symptomatic relief from these symptoms. EXAMPLE V

Ingredient % W/V

Naproxen 6.667

Pseudoephedrine HCl 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 HCl 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 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 discovery of the onset of cough, cold, cold-like and/or flu symptoms provides significantly improved symptomatic relief from these symptoms. EXAMPLE VI

Ingredient % W/V

Naproxen 6.667

Pseudoephedrine HCl 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 HCl 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 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 discovery of the onset of cough, cold, cold-like and/or flu symptoms provides significantly improved symptomatic relief from these symptoms. EXAMPLE VII

Ingredient % W/V

Naproxen 6.667

Pseudoephedrine HCl 0.200

Chlorpheniramine Maleate 0.013

Dextromethorphan HBr 0.100

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 HCl 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 dextromethorphan 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 discovery of the onset of cough, cold, cold-like and/or flu symptoms provides significantly improved symptomatic relief from these symptoms.

WHAT IS CLAIMED IS:

Claims

1. The use of a carboxylic acid represented by the following formula:

wherein R¹ is alkyl having up to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, alkoxymethyl having up to 7 carbon atoms, trifluoromethyl, vinyl, ethynyl, halo (iodo, bromo, chloro or fluoro) alkoxy having up to 6 carbon atoms, difluoromethoxy, alkoxymethoxy having up to 7 carbon atoms, alkylthio- methyloxy having up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, alkoxymethylthio having up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkylsubstituted phenyl having up to 8 carbon atoms; one of R² and R³ is hydrogen, the other being methyl, ethyl or difluoromethyl or R² or R³ together are methyl- ene; and R⁴ 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; for producing a medicament 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 human or lower animal a symptom relieving, analgesically and anti-inflammatorily effective amount of said medicament within the first 36 hours of the discovery by said human or lower animal of the onset of any of said symptoms.

2. A medicant 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 a carboxylic acid represented by the following formula:

wherein R¹ is alkyl having up to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, alkoxymethyl having up to 7 carbon atoms, trifluoromethyl, vinyl, ethynyl, halo (iodo, bromo, chloro or fluoro) alkoxy having up to 6 carbon atoms, difluoromethoxy, alkoxymethoxy having up to 7 carbon atoms, alkylthiomethyloxy having up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, al koxymethylthio having up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkylsubstituted phenyl having up to 8 carbon atoms; one of R² and R³ is hydrogen, the other being methyl, ethyl or difluoromethyl or R² or R³ together are methylene; and R⁴ 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;

3. The medicament of Claim 1 or 2 wherein said acetic acid derivative is 2-(6'-methoxy-2-napthyl) propionic acid and pharmaceutically-acceptable salts and esters thereof.

4. The medicament of Claim 3 and further wherein said medicament comprises at least one other active component selected from the group consisting of an antihistamine, decongestant, cough suppressant and expectorant and mixtures thereof.

5. The medicament of Claim 4 wherein said other active component is a decongestant, preferably said decongestant is pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, mixtures thereof or pharmaceutically acceptable salts thereof.

6. The medicament of Claim 4 wherein said other active component is a cough suppressant,preferably said cough suppressant 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. The medicament of Claim 4 wherein said other active component is a antihistamine, preferably said antihistamine is selected from the group consisting of chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, pyrilamine, acrivastine, AHR-11325, phenindamine, astemizole, azatadine, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, mixtures thereof or pharmaceutically acceptable salts thereof.

8. The medicament of Claim 4 wherein said other active component is a expectorant, preferably 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.

9. 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 human or lower animal a symptom relieving, analgesically and anti-inflammatorily effective amount of a carboxylic acid represented by the following formula:

wnerein R¹ is alkyl naving up to 6 carbon atoms, cycloalkyl having from 2 to carbon atoms, alkoxymethyl having up to carbon atoms, trifluoromethyl, vinyl, ethynyl. halo (iodo. bromo, chloro or fluoro) alkoxy having up to 6 carbon atoms, difluoromethoxy, alkoxymethoxy having up to 7 carbon atoms, alkylthio- methyloxy having up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, alkoxymethylthio having up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkylsubstituted phenyl having up to 8 carbon atoms; one of R² and R³ is hydrogen, the other being methyl, ethyl or difluoromethyl or R² or R³ together are methylene; and R⁴ is hydrogen, alkyl having up to 22 carbon atoms, unsaturated alkyl having up to 22 carbon atoms, cycloalkyl naving from 3 to 7 carbon atoms, cycloalkylmethyl having from 2 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-pnenylethyl or 3-phenylpropyl:

said composition being administered within the first 36 hours of the discovery by said human or lower animal of the onset of any of said symptoms.

10. A method according to Claim 9 wherein said acetic acid derivative is 2-(6'-methoxy-2-napthyl) prcpionic acid and pharmaceutically- acceptable salts and esters tnereof.

11. A method according to Claim 10 which comprises administering from about 100 mg to about 2000 mg of said 2-(6'-methoxy-2-napthyl) propionic acid.

12. A method according to Claim 11 wherein said 2-(6-methoxy-2-napthyl) propionic acid is administered within 24 hours of the onset of the symptoms.

13. A method according to Claim 12 wherein said pharmaceutical composition further comprises at least one other active component selected from the group consisting of an antihistamine. decongestant, cough suppressant and expectorant and mixtures thereof.

14. A method according to Claim 13 wherein said active component is a decongestant.

15. A method according to Claim 13 wherein said active component is a cough suppressant.

16. A method according to Claim 13 wherein said active component is an antihistamine.

17. A method according to Claim 13 wherein said active component is an expectorant.

18. A method according to Claim 14 wherein said decongestant is pseudoephedrine, phenyl propanol amine, phenylephrine and ephedrine, mixtures thereof or pharmaceutically acceptable salts thereof.

19. A method according to Claim 18 wherein said cough suppressant is selected from the group consisting of dextromethorphan, chlophedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, mixtures thereof or pharmaceutically acceptable salts thereof.

20. A method according to Claim 16 wherein said antihistamine is selected from the group consisting of chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, pyrilamine, acrivastine, AHR-11325, phenindamine, astemizole, azatadine, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, mixtures thereof or pharmaceutically acceptable salts thereof.

21. A method according to Claim 17 wherein said expectorant is an expectorant or mucolytic such as glyceryl guaicolate, termin hydrate, ammonium chloride, N-acetylcysteine, bromhexine and ambroxol, mixtures thereof or pharmaceutically acceptable salts thereof.

22. A method according to Claim 11 which further comprises from about 50 to about 100 mg of caffeine.