AU662297B2 - Method for providing improved analgesic effect - Google Patents

Description

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OPI DATE 30/03/92 P AOJP DATE 14/05/92 APPLN. ID 85384 91 PCT NUMBER PCT/1US91/06398 INTERNATIOrtAL. trrI 1-.iluIN rUHLlb iU UNUER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/04021 A61K 31/19 (A61K 31/19 Al /19 (A35) (43) International Publication Date: 19 March 1992 (19.03.92) (21) International Application Number: PCT/US91/06398 (81) Designated States: AU, CA, JP, KR.

(22) International Filing Date: 9 September 1991 (09.09.91) Published With international search report.

Priority data: Before the expiration of the time limit for amending the 580,685 11 September 1990 (11.09.90) US claims and to be republished in the event of the receipt of amendments.

(71) Applicant: RICHARDSON VICKS INC. [US/US]; One Far Mill Crossing, Shelton, CT 06484 (US).

(72) Inventor: SORRENTINO, James, Vincent; 88 Spoonwood Road, Wiiton, CT 06897 (US).

(74) Agent: REED, David; The Procter Gamble Company, Ivorydale Technical Ctr., 5299 Spring Grove Ave., Cincinnati, OH 45217-1087 (US).

(54)Title: METHOD FOR PROVIDING IMPROVED ANALGESIC EFFECT (57) Abstract A method for providing improved analgesic and/or anti-inflammatory effect by administering a safe and effective amount of a composition comprising a naphthalene derivative along with a sympathomimetic amine.

FOR THE PURPOSES OF INFORMATION ONLY Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.

AT Austriai AU Australia BB Barhadus BE Belgiumn BF Burkina Faso BC Bulgaria Bi Buini BR Brayil CA Canada CF Central Africani Republic CC Congo CH- Switzerland CI ('6tu d'Ivoire CM Cameroon CS Czechoslovakia DE* German~y DK Dennmark ES Spain F) 17inland FR fFrancu CA G~abon GB United IKingdon CN Guinea CR Grece HU Hungary IT Italy Jr Japan KP Demrocratic People's Republic of Korea KR Republic or K-orea LI Liechtenstein LK Sri I-anka LU Luembourg MC Monaco MC Madagascar ML Mali MN Mongolia M R Mauritania M W Malawi N L Netherlands NO Norway P L Poland RO Romania S D Sudan SE Sweden SN Senegal 5UJ+ Soviet Union TD Chad TC Togo us United Status or Anmerica Any designation of "1SU" has effect in the Russian Federation. It is not yet known whether any such designation has effe~t in other States of the former Soviet Union.

WO 92/04021 PCT/US91/06398 METHOD FOR PROVIDING IMPROVED ANALGESIC EFFECT TECHNICAL FIELD The present invention relates to a method for providing improved analgesic and/or anti-inflammatory effect by administering a safe and effective amount of a composition comprising a naphthalene derivative along with a sympathomimetic amine.

BACKGROUND OF THE INVENTION Inflammation, or the "inflammatory response", is the result of comoplex interconnected physiological events, including increased vascular permeability, fluid accumulations, and the migration of a cnanging population of inflammatory cells into the inflamed area. The clinical manifestations of inflammation include swelling (eoema), increased local temperature, erythema, ano pain. The inflammatory response can be triggered by any of a number of causative factors, including certain bacteria, radiation, hypersensitivity to chemical agents, arthritis-like conditions, and the like. The inflammatory response is generally believed to be a primary defense mechanism in the body, but, unchecked, can become excessive and can result in functional impairment.

The use of non-steroidal anti-inflammatory, anti-pyretic and analgesic drugs, especially the salicylates, which include aspirin and aspirin derivatives, to combat inflammation and attendant pain is acceoted medical practice. The non-steroidals are commonly empioyea to relieve pain and inflammation associated with, for example, bursitis, arthritis, and the like.

While pain is incapable of precise definition due to its basically subjective nature, it can generally be said that the term refers to feelings of distress or suffering caused by stimulation of soecialized nerve endings. A great variety of drugs have been developed to reduce pain in man and other animals; some directed to eliminating pain at its source, and others directed to blocking the perception of pain by the brain. Among the latter group of drugs that are designed to block the sensation of pain, are the analgesics, which generally relieve 3 pain without causing unconsciousness. Analgesics can be further classified into two main categories: opioid analgesics, including morphine, codeine, levorphanol, and the morphine-like analgesics j A WO 92/04021 PC/US91/0639S -2merperidine, and methadone; and antipyretic analgesics, such as aspirin, ibuprofen, phenacetin, acetaminophen, phenylbutazone, and indomethacin.

Although the precise pharmacological action of these analgesics is uncertain, there are certain effects which readily distinguish the opioid analgesics from the antipyretics. In particular, the antipyretics are weak analgesics, with much of their effect in the peripheral nervous system, so that behavioral changes do not usually occur.

Generally, these analgesics relieve only pain originating from muscles, joints, tendons and fasciae, and are ineffective against deep visceral pain. However, the opioid analgesics are quite effective against all types of pain, with broad-based action in the central nervous system. Aside from potent analgesia, the opioids, also known as narcotics, often produce effects on mood and other behavioral changes. Perhaps the most notable side '"fect of opioid ialgesics is the fact that their repeated use is asso,.,ated with tolerance, as well as psychic and physical dependence.

Naproxen ((+)-2-(6c-methoxy-naphthyl) propionic acid), a nonsteroidal 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 excluding aspirin, acetaminophen and phenacetin) in the preparation of cough/cold pharmaceutical compositions containing sympathomimetic amines, has been disclosed in, for example, U.S. Patent 4.552,899 to Sunshine et al. issued November 12, 1985.

Surprisingly, the present inventor has found that selected compositions comprising certain naphthalene derivatives in combination with sympathomimetic amines provide improved analgesic and/or antiinflammatory effect.

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WO 92/04021 PCT/US91/06398 q -3- SUMMARY OF THE INVENTION The present invention relates to a method of eliciting a sus- Stained, enhanced analgesic response in a human or lower animal in need of such treatment, comprising administering to such human or lower animal a safe and effective amount of a composition comprising: a) from about 10% to about 95% of a carboxylic acid represented by the following formula: 2 3

R

COOR

4 (1) R' 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, alkoxymethylthio having up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkylsubstituted 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; and R 4 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; and b) from about 5% to about 90% of one or more of a sympathomimetic amine.

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

WO 92/04021 PCT/US91/06398 I -4- DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method of eliciting a sustained, enhanced analgesic response in a human or lower animal in need of such treatment, comprising administering to such human or lower animal a safe and effective amount of a composition comprising a naphthalene derivative, preferably a 2-(6'-substituted-2'-naphthyl)-acetic acid derivative, and salts and esters thereof along with a sympathomimetic amine.

The naphthalene derivatives 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: 2 3 II COOR

R

(I)

In the above formula, R' is alkyl having up to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, alkoxymethyl having up to 7 carbon atoms, tr fluoromethyl, 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, alkoxymethylthio naving up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkylsubstituted 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

4 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 carbon atoms, 3-cyclopentylpropyl, 3-cyclohexylpropyl, benzyi, 2-phenylethyl or 3-phenylpropyl.

r ct WO 92/04021 PCT/US91/06398 Preferably, the 6'-substituent (represented by R' in the above formula) is methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, ethoxy, methoxymethyloxy, difluoromethoxy, methylthio, ethylthio, methoxymethylthio, difluoromethylthio or phenyl; one of R 2 and R 3 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 and 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 "insaturated 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, ethoxymethloxy, 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 methylthiomethylthio, ethylthiomethylthio and the like.

ti SWO 92/04021 PCT/US91/06398 -6- The term "alkoxymethylthio" refers to methylthio ether groups substituted with an alkoxy group such as methoxymethylthio, ethoxymethylthio, 2-propoxymethylthio and the like.

The term "aryl" refers to phenyl, or m- and/or p- alkylsubstituted phenyl derivatives such as phenyl, o-tolyl, 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, cyclopentylmethyl, 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-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl and 2-cycloheptylethyl.

The most preferred compound used herein is (+)-2-(6a-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 Slike. Salts derived from pharmaceutically acceptable organic nontoxic 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 triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lyrine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobromine, purines, piperazine, piperidine, polyamine 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 enantiomorphs or optical isomers. Each enantiomorph and mixtures thereof are included within the present irvention. 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 1 c ;r ~ii. .i WO 92/04021 PCT/US91/06398 -7some 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 as 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.

Sympathomimetic amines are a well-known class of drugs which activate adrenergic receptors. These drugs are fully described in Respiratory Pharmacology and Therapeutics, Ziment, Saunders Company (1978), pp. 316-339, which is incorporated by reference herein. Drugs that are particularly preferred for use herein are those which are known to stimulate the alpha adrenergic receptors.

The sympathomimetic amines useful herein include pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, their pharmaceutically acceptable salts, and mixtures thereof.

Preferably, the pharmaceutical compositions of the present invention comprise the naphthalene derivative and sympathomimetic amine in a ratio of naphthalene derivative:sympathomimetic amine 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, gelcaps 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 WO 92/04021 PCT/US91/06398 -8and 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, tablet triturates, 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.

Liquid oral dosage forms include aqueous and nonaqueous solutions, 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 Science _s (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 Vu-. 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 microcrystalline cellulose/sodium carboxymethyl cellulose mixture F- WO 92/04021 PT/US91/06398 -9available from FMC), gu-r 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 .,eight/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 j 15 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 cough suppressant such as dextromethorphan, chlophedianol, carbetapentane, caramiphei, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, their pharmaceutically-acceptable salts; an expectorant or mucolytic such as glyceryl guaiacolate, terpin, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their 1 pharmaceutically acceptable salts; and an antihistamine such as chlorpheniramine brompheniramine, dexchlorpheniramine, dexbrompheniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, phenindamine.

pyrilamine, azatadine, their pharmaceutically acceptable salts, as well as the non-sedating antihistamines which include acrivastine, I AHR-11325, phenindamine, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, 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, WO 92/04021 PCT/US91/06398 which are incorporated by reference herein. Also useful are bronchodilators such as theophylline and albuterol. A highly preferred optional component is caffeine, which is preferably present at a level of from about 10% to about 50%. C Fe~ prl-~Pee \y p-s o.' Other optional ingredients well known to the pharmacist'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 product, antioxidants, for example, butylated hydroxy anisole or butylated hydroxy toluene, and preserva' les, for example, methyl or propyl paraben or sodium benzoate, to .olong 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, expectorant and/or antihistamine required per dose, stability, -elease 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 scribed nerein. This amount can be given in a single dose, or, pre;erably, 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 So 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 following examples illustrate embodiments of the subject invention wherein both essential and optional ingredients are combined.

A

i WO 92/04021 PCT/US91/06398 -11- 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 selected capsule size.

Administration of two of the above capsules to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect.

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 HCL 30 mg Glyceryl guaiacolate 100 mg Triturate active ingredients and q.s. with lactose to selected capsule size.

Administration of two of the above capsules to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect.

EXAMPLE III A liquid composition for oral administration is prepared by combining the following ingredients: Ingredient W/V Naproxen 6.667 Pseudoephedrine HC1 0.200 Alcohol 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 WO 92/04021 PCT/US91/06398 -12- 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 HCI are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then added. In a seperate container the colorance are added to purified water (approximately 0.5% of the final batch volume). This colorance 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 to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect.

EXAMPLE IV A liquid composition for oral administration is prepared by combining the following ingredients: Ingredient W/V Naproxen 6.667 Pseudoephedrine HCI 0.200 Chlorpheniramine Maleate 0.013 Alcohol 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 HCI and chlorpheniramine maleate are added sequentially and dissolved with agitation. The i 35 glycerin and liquid sugar are then added. In a seperate container the colorance are added to purified water (approximately 0.5% of the final Si WO 92/04021 PC/US91/06398 i* -13batch volume). This colorance 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 to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect.

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 Chlorpheniramine Maleate 0.013 Dextromethorphan HBr 0.100 Alcohol 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 HCI and chlorpheniramine maleate are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then added. In a seperate container the colorance are added to purified water (approximately 0.5% of the final batch volume). This colorance 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.

I

i. r WO 92/04021 PCT/US91/06398 -14- 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 to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect.

1I.t IJ :L:.IrIEE j)1~ 47 "i I

Claims (14)

1. A method of eliciting a sustained, enhanced analgesic response in a human or lower animal in need of such treatment, comprising administering to such human or lower animal a safe and effective amount of a composition comprising: a) from "aBot 10% to ab-ee 95% of a carboxylic acid represented by the following formula: COOR 4 R 2 "1 (I) R' is alkyl having up to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, alkoxymethyl having up to 7 carbon atoms, tri- fluoromethyl, 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, alkoxymethylthio having up to 7 carbon atoms, cyano di- fluoromethylthio, phenyl or alkylsubstituted phenyl having up to 20 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 methyl- ene; and R 4 is hydrogen, alkyl having up to 22 carbon atoms, unsaturated alkyl having up to 22 carbon atoms, cycloalkyl having 9 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-cyclopen- tylethyl having from 5 to 10 carbon atoms, 3-cyclopentylpropyl,

3-cyclohexylpropyl, benzyl, 2-phenylethyl or 3-phenylpropyl; and b) from abou 5% to aMeB t 90% of one or more of a sympath- 30 omimetic amine. 2. A method accoroing to Claim 1 wherein said acetic acid derivative is 2-(6a-methoxy-2-napthyl) propionic acid and pharmaceutically- acceptable salts and esters thereof. -16- 3. A method according to Claim 2 which comprises administering from about 100 mg to about 2000 mg of said 2-(6a-methoxy-2-naphthyl) propionic acid.

4. A method according to Claim 3 wherein said sympathomimetic amine is selected from the group consisting of pseudoephedrine, phenyl- propanolamine, phenylephrine and ephedrine, mixtures thereof or pharmaceutically acceptable salts thereof. A method according to Claim 4 wherein the ratio of naphthalene derivative to sympathomimetic amine ranges from about 200:1 to about 1:1.

6. A method according to Claim 5 which comprises from about 50 mg to about 2000 mg of said pharmaceutical composition.

7. A method according to Claim 6 which comprises from about 100 mg to about 2000 mg of said pharmaceutical composition.

8. A method according to Claim 5 wherein said pharmaceutical compo- sition further comprises at least one other active component i selected from the group consisting of an antihistamine, cough suppressant and expectorant and mixtures thereof. «t

9. A method according to Claim 8 wherein said active component is an °cough suppressant. *44 A method according to Claim 8 wherein said active component is a antihistamine.

11. A method according to Claim P wherein said active ccmponent is an expectorant. i 1 i -17-

12. A method according to Claim 9 wherein said cough suppressant is selected from the group consisting of dextromethorphan, chlophe- dianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone. hydromorphone, fominoben, mixtures thereof or pharmaceutically acceptable salts thereof.

13. A method according to Claim 10 wherein said antihistamine is selected from the group consisting of chlorpheniramine brom- pheniramine, dexchlorpheniramine, dexbromphreniramine, tripro- lidine, doxylamine, tripelennamine, cyproheptadine, carbinox- camine, bromodiphenhydramine, phenindamine, pyrilamine, azatadine, acrivastine, AHR-11325, phenindamine, astemizole, azatadine, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, lorati- dine, levocabastine, mequitazine, oxatomide, setastine, tazi- fylline, temelastine, and terfenadine, mixtures thereof or pharmaceutically acceptable salts thereof.

14. A method according to Claim 11 wherein said expectorant is an expectorant or mucolytic such as glyceryl guaiacolate, terpin, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, mixtures thereof or pharmaceutically acceptable salts thereof. A method according to Claim 12 which further comprises from about S" 50 to about 100 mg of caffeine.

16. A method according to Claim 13 which further comprises from about o* 50 to about 100 mg of caffeine. *o 17. A method according to Claim 14 which further comprises from about 50 to about 100 mg of caffeine. DATED: 23 March 1993 PHILLIPS ORMONDE FITZAATRICK Attorneys for: C RICHARDSON VICKS INC. i; 1 Ii ii V C1~ASS1FICAT1ON OF Stil INTERNATIONAL SEARCH REPORT International Application No P CT/US 91/06398 IJECT MATTER (If several clasification symbols apply, indicate all) 6 According to International Patent Classification (fl'C or to both National Classification and IPC Int. C1.5 A 61 K 31/19 61 K 31/19 A 61 K 31: 135) H. FIELDS SEARCHED Minimumo Documentation Searched' Clssification System Classification Symbols Int.Cl.5 A 61 K Doctumentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searcheds MU. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category 0 Citation of Document, 11 with Indication, where appropriate, of the relevant passages 12 Relevant to Claim No.3 A WO,A,8504589 (SUNSHINE A. et al.) 24 1-10 October 1985, see claims 1,3,15 (cited in the appl ication) A WO,A,850254O (RICHAROSON-VICKS, 1-10 INC.) 20 June 1985, see the abstract A W0,A,8503443 (RICHAROSON-VICKS, 1-10 INC.) 15 August 1985, see claim A 0Special categories of cited documents 10 1-17 later document publIshed after the international filing date ocuentdefiingthegenral tat ofthein ih~c isnotor priority date and not In conflict with the application hut A' dcumnt efinng he enerl rsteof te at ihlchIs ottite to understand the principle or theory underlying the considered to be of particuslar reltvance Invention earlier document but published on or after the ilitternatlonal x'r document of particular relevance; the claimed Invention filing date cannot be considered novel or cannot he considered to document which may throw doubts on priority clsim(s) or Involve an1 Inventive Step which Is cited to establish the publication date of another document of particular releyance; the claimed Invention citation or other special reason (as specified) cannot be considered to Involve an Inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other s.ch docu- other means ments, such combination being obvious to a person skilled Oocument published prior to the International filing date hot in the art. later than the priority date claimed W document member of the tame patent family IV. CETFCATION Date of the Actual Completion of the International Searcht Date of Milling of this International Search Report

19-12-1991 3 1. 91. 92 International Searching Authority 1 Sinatu{ fAut'horie O EUOEAN PATENT OFFICE J 4~~TNE Porin PCTIISAf11 (mooed &beet) (Jeniny IM1) International Application No. PCTI US91 106398 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET V. M OBSERVATION WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE 1 This International search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. M Claim numbers because they relate to subject matter not required to be searched by this Authority, namely. Claims searched incompletely: 3 Claims not searched:13-27 See PCT-Rule 39.1 methods for treatment of the human or animal body by surgery or therapy as.we-11 as diagnostic methods 2. -I Claim numbers because they relate to parts of the International application that do not comply with the prescribed requirements to such an extent that no meaningful International search can be camed out, specifically. Claims searched incompletely: 1,2,3 Reason: as the formula of claim 1 and 2 covers too many components, the search has been performed on the general idea and active agents mentioned in the claims and description. (EP: art 84, Guidelines.. Part B, Chapter 11.7 last sentence and chapter III, 3.7) 3. O Claim numbers because they are dependent claims and are not drafted in accordance with the second and third sentences of PCT Rule 6.4(a). VI. OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING 2 This International Searching Authority found multiple Inventions in this International application as follows: 1. II As all required additional search fees were timely paid by the applicant, this International search report covers all searchable claims of the International application 2. -I As only some of the required additional search fees were timely paid by the applicant, this International search report covers only those claims of the International application for which fees were paid, specifically claims: 3. No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims: It is covered by claim numbers: 4. As all searchable claims could be searched without effort justifying an additional fee, the International Searching Authonty did not Invite payment of any additional fee. Remark on Protest The additional search fees were accompanied by applicant's protest. O No protest accompanied the payment of additional search fees. Form PCT/ISA/210 (supplemental sheet P9412B 05/91 ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. US 9106398 SA 51528 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 21/01/92 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) date WO-A- 8504589 24-10-85 US-A- 4552899 12-11-85 AU-B- 589554 19-10-89 AU-A- 4120085 01-11-85 CA-A- 1258430 15-08-89 EP-A- 0180597 14-05-86 JP-T- 61501913 04-09-86 US-A- 4749697 07-06-88 US-A- 4839354 13-06-89 US-A- 4749722 07-06-88 US-A- 4749711 07-06-88 US-A- 4749723 07-06-88 US-A- 4749720 07-06-88 US-A- 4749721 07-06-88 US-A- 4783465 08-11-88 US-A- 4920149 24-04-90 US-A- 4840962 20-06-89 US-A- 4871733 03-10-89 US-A- 5025019 18-06-91 US-A- 4619934 28-10-86 US-A- 4738966 19-04-88 WO-A- 8502540 20-06-85 US-A- 4558051 10-12-85 AT-B- 389999 26-02-90 AT-B- 389997 26-02-90 AU-B- 574419 07-07-88 AU-A- 3747485 26-06-85 CA-A- 1246453 13-12-88 CH-A- 669730 14-04-89 DE-T- 3490583 03-04-86 EP-A,B 0165308 27-12-85 GB-A,B 2161076 08-01-86 JP-T- 61500665 10-04-86 NL-T- 8420316 01-11-85 SE-A- 8503762 09-08-85 WO-A- 8503443 15-08-85 US-A- 4522826 11-06-85 AT-B- 390878 10-07-90 AU-B- 576825 08-09-88 AU-A- 3935685 27-08-85 o 0 b For more details about this annex see Official Journal of the European Patent Office, No. 12/82 I ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. Page 2 US 9106398 SA 51528 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 21/01/92 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) date A~ WO-A- 8503443 BE-A- 901667 29-05-85 CA-A- 1251137 14-03-89 CH-A- 667392 14-10-88 DE-T- 3590035 13-03-86 FR-A,B 2559061 09-08-85 GB-A,B 2162747 12-02-86 NL-T- 8520027 02-01-86 SE-A- 8504612 04-10-85 US-A- 4755532 05-07-88 US-A- 4906625 06-03-90 US-A- 4985459 15-01-91 US-A- 4585783 29-04-86 US-A- 4683243 28-07-87 o *S For more details about this annex see Official Journal of the European Patent Office, No. 12/82