AU663857B2 - Dextromethorphan antitussive compositions - Google Patents

Description

OPI DATE 26/05/92 AOJP DATE 09/07/92 INTERN A i iln .i APPLN. ID 89158 91 PCT NUMBER PCT/US91/07773 N TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/07559 A61K 31/05, 31/485, 9/00 Al (43) International Publication Date: 14 May 1992 (14.05.92) (21) International Application Number: PCT/US91/07773 (81) Designated States: AT, AT (European patent), AU, BB, BE (European patent), BF (OAPI patent), BG, BJ (OAPI (22) International Filing Date: 21 October 1991 (21.10.91) patent), BR, CA, CF (OAPI patent), CG (OAPI patent), CH, CH (European patent), CI (OAPI patent), CM Priority data: (OAPI patent), CS, DE, DE (European patent), DK, 606294 31 October 1990 (31.10.90) US DK (European patent), ES, ES (European patent), FI, FR (European patent), GA (OAPI patent), GB, GB (Eu- (71) Applicant: THE PROCTER GAMBLE COMPANY ropean patent), GN (OAPI patent), GR (European pa- [US/US]; One Procter Gamble Plaza, Cincinnati, OH tent), HU, IT (European patent), JP, KP, KR, LK, LU, 45202 LU (European patent), MC, MG, ML (OAPI patent), MN, MR (OAPI patent), MW, NL, NL (European pa- (72) Inventor: SMITH, Ronald, Lee 6303 Runabay Court, tent), NO, PL, RO, SD, SE, SE (European patent), SN West Chester, OH 45069 (OAPI patent), SU+,TD (OAPI patent), TG (OAPI patent).

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

Before the expiration of the time limit for amending the claims and to be republished in the event of the receipt of amendments.

663 857 (54) Title: DEXTROMETHORPHAN ANTITUSSIVE COMPOSITIONS (57) Abstract The subject invention involves antitussive pharmaceutical compositions for the peroral administration of dextromethorphan, the composition being at a pH of from about 8 to about 11.

:1 i ,'uit See back of page .~---ra~laaui7sg~;~rwmas WO 92/07559 PCT/US91/07773 -1- DEXTROMETHORPHAN ANTITUSSIVE COMPOSITIONS TECHNICAL FIELD This invention is concerned with novel antitussive compositions containing dextromethorphan. More particularly, it is concerned with compositions and methods for rapidly achieving therapeutic systemic levels of dextromethorphan.

BACKGROUND OF THE INVENTION Dextromethorphan (racemethorphan), 3-methoxy-17-methylmor- H phinan, is disclosed in the Merck Index, 10th edition (1983), M.

Windholz, ed., No. 8009, p. 1170; it is disclosed to be an antitussive agent.

Dextromethorphan hydrobromide is used extensively as an S antitussive agent in commercial products as disclosed in the Physician's Desk Reference for Nonprescription Drugs, 11th Edition (1990), E.R. Barnhardt, pub., p. 306, and in Physician's Desk Reference, 44th Edition (1990), E.R. Barnhardt, pub., p.

309: Bayer Children's Cough Syrup by Glenbrook, Benylin DM by Parke-Davis, Benylin Expectorant by Parke-Davis, Cerose-DM by Wyeth-Ayerst, Cheracol D Cough Formula by Upjohn, Cheracol Plus Head Cough/Cold Formula by Upjohn, Cough Formula Comtrex by Bristol-Myers Products, Comtrex Multi-Symptom Cold Reliever Tablets/Caplets/Liquid/Liquigels by Bristol-Myers Products, Contac Cough Formula by SmithKline Consumer, Contac Cough Sore Throat Formula by SmithKiline Consumer, Contac Jr. Children's Cold Medicine by SmithKline Consumer, Contac Nighttime Cold Medicine by SmithKline Consumer, Contac Severe Cold Formula Caplets by SmithKline Consumer, Dimacol Caplets by Robins, Dorcol Children's Cough Syrup by Sandoz Consumer, Hold by SmithKline Beecham, Naldecon DX Adult Liquid by Bristol Laboratories, :1 Naldecon DX Children's Syrup by Bristol Laboratories, Naldecon DX Pediatric Drops by Bristol Laboratories, Naldecon Senior DX Cough/Cold Liquid by Bristol Laboratories, Novahistine DMX by Lakeside Pharmaceuticals, Pediacare Cough-Cold Formula Liquid and Chewable Tablets by McNeil Consumer Products, Pediacare Night i WO 92/07559 PCT/US91/07773 -2 Rest Cough-Cold Formula Liquid by McNeil Consumer Products, Robitussin Night Relief by Robins, Robitussin-CF by Robins, Robitussin-DM by Robins, Scot-Tussin Sugar-Free DM Cough Cold Medicine by Scot-Tussin, Snaplets-DM by Baker Cummins Pharmaceuj 5 ticals, Snaplets-Multi by Baker Cummins Pharmaceuticals, St.

Joseph Cough Suppressant for Children by Plough, St. Joseph j Nighttime Cold Medicine by Plough, Sucrets Cough Control Formula by SmithKline Beecham, Sudafed Cough Syrup by Burroughs Wellcome, Triaminic Night Light by Sandoz Consumer, Triaminic-DM Syrup by Sandoz Consumer, Triaminicol Multi-Symptom Cold Tablets by Sandoz j Consumer, Triaminicol Multi-Symptom Relief by Sandoz Consumer, Tylenol Cold Medication Caplets and Tablets by McNeil Consumer Products, Tylenol Cold Medication Liquid by McNeil Consumer Products, Tylenol Cold Medication No Drowsiness Formula Caplets by McNeil Consumer Products, Vicks Children's Cough Syrup by Richardson-Vicks, Inc., Vicks Children's NyQuil by Richardson- Vicks, Inc., Vicks Cough Silencers Cough Drops by Richardson- Vicks, Inc., Vicks Daycare Daytime Colds Medicine Caplets by Richardson-Vicks, Inc., Vicks Daycare Multi-Symptom Colds Medicine Liquid by Richardson-Vicks, Inc., Vicks Formula 44 Cough Control Discs by Richardson-Vicks, Inc., Vicks Formula 44 Cough Medicine by Richardson-Vicks, Inc., Vicks Formula 44D Decongestant Cough Medicine by Richardson-Vicks, Inc., Vicks Formula 44M Multi-Symptom Cough Medicine by Richardson-Vicks, Inc., Vicks NyQuil Nighttime Colds Medicine-Original Cherry Flavor by Richardson-Vicks, Inc., Vicks Pediatric Formula 44 Cough Medicine by Richardson-Vicks, Inc., Vicks Pediatric Formula 44 Cough Colds Medicine by Richardson-Vicks, Inc., Vicks Pediatric Formula 44 Cough Congestion Medicine by Richardson- Vicks, Inc., Ambenyl-D Decongestant Cough Formula by Forest Pharmaceuticals, Bromarest DX Cough Syrup by Warner Chilcott, BromFed-DM Cough Syrup by Muro, Codimal DM by Central Pharmaceu- Sticals, Dimetane-DX Cough Syrup by Robins, Guaifenesin w/D-Methorphan Hydrobromide Syrup by Lederle, Humibid DM Tablets by Adams, IoTuss-DM Liquid by Muro, Medi-Tuss DM by Warner Chilcott, Phenergan with Dextromethorphan by Wyeth-Ayerst, TI r -7 WO 92/07559 PCT/US91/07773 3 Poly-Histine DM Syrup by Bock, Quelidrine Syrup by Abbott, Rondec-DM Oral Drops by Ross, Rondec DM Syrup by Ross, Tusibron- DM by RAM Laboratories, Tussar DM by Rorer Pharmaceuticals, and Tussi-Organidin DM Liquid by Wallace. Delsym Cough Suppressant Syrup by McNeil Consumer contains dextromethorphan polistirex as an antitussive agent. It is believed that all of the above commercial products containing dextromethorphan are included in compositions at about neutral pH or lower.

Beckett, E. G. Triggs, "Buccal Absorption of Basic Drugs and Its Application as an In Vivo Model of Passive Drug Transfer Through Lipid Membranes", Journal of Pharmaceutics and Pharmacology, Vol. 19 Supplement (1967), pp. 31S-41S, discloses that buccal absorption of a number of drugs is substantially increased from compositions having a higher pH, when such compositions are held and circulated in the mouth for 5 minutes.

Dextromethorphan is not disclosed as one of those drugs tested in Beckett and Trigqs. The disclosure of Beckett and Triqqs would not be expected to be very pertinent to liquid products which are generally not held in the mouth but are swallowed quickly, or even to solid products such as lozenges which are allowed to dissolve in the mouth where the dissolution liquid is rapidly swallowed.

U. S. Patent No. 4,892,877 issued to Sorrentino on January 9, 1990, discloses liquid compositions for the treatment of coughs comprising both dextromethorphan and phenol, the compositions having a pH of 5-9. U.S. Patent No. 4,427,681 issued to Munshi on January 24, 1984, discloses thixotropic compositions for the treatment of coughs comprising both dextromethorphan and Avicel® RC-591. These patents are hereby incorporated by reference.

SUMMA-RY OFTHE INVENTIOrN It is ect of the subject invention to provide dextromethorphan compositions o al administration which will provide more rapid antitussive action than c esill available imia~ ~1~1"1~ 1 i a Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives or components or integers.

SUMMARY OF THE INVENTION It would be desirable to provide dextromethorphan compositions for peroral administration which will provide more rapid antitussive action than commercially available compositions.

It would also be desirable to provide methods for achieving rapid antitussive action from dextromethorphan compositions.

The subject invention involves pharmaceutical compositions for oral administration which comprises a safe and effective amount of dextromethorphan and an orally-acceptable pharmaceutical carrier, the composition having a pH of from about 8 to about 11.

The subject invention also involves pharmaceutical compositions for oral administration which comprise a safe and effective amount of dextromethorphan, safe and effective amounts of cough/cold dru'g actives other than phenol, and an orally-acceptable pharmaceutical carrier, the composition having a pH of from about 8 to about 11.

The subject invention also involves pharmaceutical compositions for oral administration which comprise a safe and effective amount of dextromethorphan, a safe and effective amount of phenol, and an orally-acceptable pharmaceutical carrier, the composition having a pH of from greater than 9 to about 11.

The term "peroral" as used herein in both the description and claims means administration through the mouth and includes administration of liquid compositions such as syrups, elixirs, suspensions, sprays and drops. It also includes administration of solid compositions which are dissolved or masticated in the mouth such as lozenges chewable lozenges, powders and chewable tablets.

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Im- -7 WO 92/07559 PCT/US91/07773 4 It is also an object f the ubject inventioe i e methods for achieving rapid antitussive n from dextromethorphan compositions.

The sb inenvention involves pharmaceutical compositions s i hich .s cnsist esse&ental1y of a safe and Sfective amount of dextromethorphan and an orally-acceptable pharm eutical carrier, the composition having a pH of from about 8 to abou 1.

Sii The subje invention also involves pharmaceutical compositions for oral admi tration which comprise a safe and effective Samount of dextromethorkn, safe and effective amounts of Scough/cold drug actives othertan phenol, and an orally-acceptable pharmaceutical carrier, the c mosition having a pH of from about 8 to about 11.

The subject invention also involves pharaceutical compositions for oral administration which comprise a sa feand effective amount of dextromethorphan, a safe and effective aomunt of phenol, and an orally-acceptable pharmaceutical carrier the -c-omps4t4on-hav4g-a-pH of from greater than 9 to about 11.

DETAILED DESCRIPTION OF THE INVENTION The compositions and methods of the subject invention comprise a safe and effective amount of dextromethorphan, and possibly other drug actives. The phrase "safe and effective amount", as used herein, means an amount of drug active high enough to provide a significant positive modification of the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A safe and effective amount of drug active will vary with the particular condition being treated, the age and physical condition of the patient being treated, the p severity of the condition, the duration of the treatment, the nature of concurrent therapy and like factors.

Dextromethorphan is known to have pharmacological activity as an antitussive agent. As used herein, "dextromethorphan" WO 92/07559 PCT/US91/07773 means racemethorphan, 3-methoxy-17-methylmorphinan (dl-cis- 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4a-iminoethanophenanthrene:

NCH

3 and pharmaceutically-acceptable salts thereof. Preferred salts of dextromethorphan include the hydrobromide salt.

The compositions of the subject invention preferably comprise from about 1 mg to about 50 mg dextromethorphan per dose, more preferably from about 2.5 mg to about 30 mg dextromethorphan per dose. Liquid compositions preferably comprise from about 0.02% to about 1.5% dextromethorphan, more preferably from about 0.05% to about 1% dextromethorphan, most preferably from about 0.1% to about 0.3% dextromethorphan. A typical dose for a liquid antitussive composition is from about 1 ml to about 30 ml. A dose of liquid cough syrup is more typically from about 5 ml to about 20 ml, especially about 15 ml. A dose of concentrated liquid cough spray is more typically from about 2 ml to about ml, especially about 3.5 ml.

Preferred compositions of the subject invention consist essentially of a safe and effective amount of dextromethorphan, and an orally-acceptable pharmaceutical carrier, the composition having a pH of from about 8 to about 11, preferably of from about 8.4 to about 10, more preferably still of from about 8.5 to about most preferably of about 9. Other preferred compositions of the subject invention comprise a safe and effective amount of dextromethorphan, safe and effective amounts of other cough/cold drug actives other than phenol, and an orally-acceptable pharmaceutical carrier, the composition having a pH of from about 8 to about 11, preferably from about 8.4 to about 10, more preferably still from about 8.5 to about 9.5, most preferably about 9.

Other preferred compositions of the subject invention comprise a safe and effective amount of dextromethorphan, a safe and F_ WO 92/07559 PCT/US91/07773 6effective amount of phenol, and an orally-acceptable pharmaceutical carrier, the composition having a pH of from greater than 9 to about 11, preferably from about 9.5 to about also preferably from about 9.1 to about It has been found that the compositions of the subject invention result in faster attainment of therapeutic blood levels of dextromethorphan, maintenance of such therapeutic blood levels for a longer time, and/or higher peak blood levels of dextromethorphan, compared to conventional lower pH dextromethorphan compositions.

The compositions of the subject invention preferably have a basic buffering strength sufficient to overcome that provided by the saliva and mucus membranes of the mouth and throat, such that the composition mixed with saliva is retained in the above pH ranges during the period that it is in the mouth and throat.

Consequently, the compositions of the subject invention preferably have a basic buffer strength of at least about 0.01 milliequivalents (mEq) base per unit dose, more preferably from about 0.05 mEq to about 2.5 mEq per unit dose, most preferably from about 0.1 mEq to about 1.5 mEq per unit dose.

The compositions of the subject invention comprise a pharmaceutically-acceptable carrier preferably comprising a pharmaceutically-acceptable buffer system. Examples of pharmaceuticallyacceptable buffer systems useful in the compositions of the subject invention include, but are not limited to, phosphate buffer systems which are a mixture of salts of monohydrogen and dihydrogen phosphate, sodium hydroxide/glycine buffer systems, and carbonate and hydrogen carbonate buffer systems. Preferred I buffer systems useful in the compositions of the subject invention are phosphate buffer systems.

A preferred component of the carrier of the compositions of the subject invention is microcrystalline cellulose or a mixture of mycrocrystalline cellulose and carboxymethylcellulose sodium.

Microcrystalline cellulose and mixtures of microcrystalline cellulose and carboxymethylcellulose sodium are available from FMC Corporation under the trade name Avicel®. Such mixtures t:r WO 92/07559 PCT/US91/07773 7 preferably have a ratio of microcrystalline cellulose to carboxymethylcellulose sodium of from about 20:1 to about 1:1; more preferably from about 15:1 to about 3:1, more preferably still from about 10:1 to about 5:1.

A preferred mixture of microcrystalline cellulose and carboxymethylcellulose sodium is Avicel® RC591, a commercially available microcrystalline cellulose marketed by FMC Corporation, Food and Pharmaceutical Products Division, Philadelphia, Pennsylvania. Avicel® RC591 is said to be a colloidal form of about 89% microcrystalline cellulose gel blended with about 11% sodium carboxymethylcellulose which is dried; the product is easily dispersed in water. It is insoluble in water, organic solvents and dilute acids. It is partially soluble in dilute alkali. Its chemical and physical specifications are as follows: loss on drying: less than 6% at time of shipment; heavy metals: less than parts per million; viscosity of a 1.2% solution: 65 1%; particle size: less than 0.1% retained on 60 mesh screen, less than 20% retained on a 325 mesh screen. Average particle size is about 28 microns. Its bulk density is about 37 Ibs/ft 3 loose pack and about 52 lbs/ft 3 tight pack. Its specific gravity is 1.55, ash content about pH of a 2% dispersion in water is 6 to 8. The product is described more fully in FMC Corporation bulletin L-318 "Avicel® RC-CL Microcrystalline Cellulose" which is incorporated herein by reference.

The quantity of microcrystalline cellulose or mixture of microcrystalline cellulose and carboxymethylcellulose sodium incorporated in the compositions of the subject invention is preferably from about 0.5% to about more preferably from about 1% to about more preferably still about The compositions of the subject invention are intended for 4 peroral administration. Examples of such compositions include preferred liquid compositions, especially aqueous-based liquid compositions, such as syrups, elixirs, suspensions, sprays, and drops. Also preferred are solid compositions which are dissolved or masticated in the mouth such as lozenges, chewable lozenges, powders, and chewable tablets. The pH of such solid dosage forms j, r WO 92/07559 PCT/US91/07773 -8 is determined by dissolving the solid dosage form in artificial saliva at a concentration of 10% of the solid composition and determining the pH of the resulting solution or suspension.

(Artiffiial saliva formulation is disclosed in Fusayema, T.

Katayori S. Nomoto, "Artificial Saliva", Journal of Dental Research, Vol. 42 (1963), pp. 1183-1197, which is incorporated herein by reference).

Dextromethorphan is relatively insoluble in water at the pH of the compositions of the subject invention. Therefore, it is preferable that sufficient levels of one or more cosolvents be incorporated in the carrier to provide for dissolution of the dextromethorphan in the composition and in the oral cavity.

Preferred cosolvents for this purpose include ethanol, propylene glycol, polyethylene 1lycol, glycerin and sorbitol; more preferred cosolvents include ethanol, propylene glycol and glycerin.

For the liquid compositions of the subject invention, the carrier preferably includes some of the following optional ingredients: water; sweetening agents, such as sucrose, corn syrup, invert sugar, dextrose, sodium saccharin, aspartame, sorbitol, honey, and magnasweet; aromatic ingredients, such as menthol, anethol, camphor, thymol, methyl salicylate, eucalyptus oil and peppermint oil; other flavoring agents; thickening agents, such as carboxymethylcellulose, sodium carboxymethylcellulose, cellulose, glycerine and polyethylene glycol; coloring agents; preservatives, such as sodium benzoate and cetylpyridinium chloride; miscellaneous ingredients, such as potassium sorbate, sodium chloride, titanium dioxide, polysorbate sodium citrate, sodium bicarbonate, sodium hydroxide, aluminum hydroxide and magnesium hydroxide.

In the solid compositions of the subject invention, the carrier preferably includes one or more of the optional ingredients provided hereinabove for the liquid compositions, and 4 additionally the following optional ingredients may be included in such compositions: solid diluents, binders, disintegrants and opacifiers, such as silicon dioxide, talc, povidone, Kaolin, dicalcium phosphate, calcium sulfate, lactose and starch; and i i -i

L

7F WO 92/07559 PCT/US91/07773 -9miscellaneous ingredients, such as acacia, capsicum, mannitol, sodium alginate, alginic acid, veegum, guar gum, gelatin, ethylcellulose, magnesium stearate, bentonite and sodium lauryl sulfate.

The compositions of the subject invention also may comprise one or more other active drug agents useful for treating coughs and/or colds (cough/cold drug actives). Cough/cold drug actives commonly combined with antitussive agents in commercial products are preferred. Cough/cold drug actives useful in the compositions of the subject invention include antihistamines, bronchodilators, decongestants, expectorants, local anesthetics and anti-inflammatory/analgesics. Preferred examples of such optional drug actives and preferred amounts per unit dose in the compositions of the subject invention include the following: antihistamines, such as chlorpheniramine (preferably from about 1 mg to about 8 mg, more preferably from about 2 mg to about 4 mg) Sand its salts maleate), diphenhydramine (preferably from Sabout 6 mg to about 50 mg, more preferably from about 12 mg to about 25 mg) and its salts hydrochloride), brompheniramine (preferably from about 1 mg to about 8 mg, more preferably from about 2 mg to about 4 mg) and its salts, doxylamine (preferably from about 2 mg to about 20 mg, more preferably from about 6 mg to about 12 mg) and its salts succinate), triprolidine (preferably from about 0.5 mg to about 4 mg, more preferably from about 1 mg to about 3 mg) and its salts hydrochloride); bronchodilators, such as ephedrine (preferably from about 5 mg to about 50 mg, more preferably from about 10 mg to about 25 mg) and its salts hydrochloride, sulfate), decongestants, such as pseudoephedrine (preferably from about 10 mg to about 100 mg, more preferably from about 30 mg to about 60 mg) and its salts hydrochloride), phenylephrine (preferably from about 2 mg to about 20 mg, more preferably from about 5 mg to about 10 mg) and its salts hydrochloride), phenylpropanolamine (preferably from about 5 mg to about 50 mg, more preferably from about 12 mg to about 25 mg) and its salts hydrochloride); expectorants, such as guaifenesin (preferably from about 50 mg to Lr-: i ri~aa -DI--D1-n*a~ WO 92/07559 PC'~/US91/07773 about 400 mg, more preferably from about 100 mg to about 200 mg); local anesthetics, such as benzocaine, (preferably from about 1 mg to about 25 mg, more preferably from about 2 mg to about mg), phenol (preferably from about 10 mg to about 150 mg, more preferably from about 20 mg to about 50 mg), dyclonine (preferably from about 1 mg to about 10 mg, more preferably from about 2 mg to about 4 mg) and its salts hydrochloride), lidocaine (preferably from about 2 mg to about 20 mg, more preferably from about 4 mg to about 10 mg) and its salts hydrochloride), butacaine (preferably from about 5 mg to about 50 mg, more preferably from about 10 mg to about 20 mg) and its salts (e.g.

sulfate, hydrochloride), benzyl alcohol (preferably from about mg to about 750 mg, more preferably from about 100 mg to about 500 mg), dibucaine (preferably from about 0.1 mg to about 4 mg, more preferably from about 0.5 mg to about 2 mg) and its salts hydrochloride), tetracaine (preferably from about 0.1 mg to about 4 mg, more preferably from about 0.5 mg to about 2 mg) and its salts hydrochloride), phenolate sodium (preferably from about 10 mg to about 150 mg, more preferably from about mg to about 50 mg), salicyl alcohol (preferably from about 20 mg to about 200 mg, more preferably from about 50 mg to about 100 mg), hexylresorcinol (preferably from about 1 mg to about 10 mg, more preferably from about 2 mg to about 4 mg), and menthol (preferably from about 2 mg to about 50 mg, more preferably from about 5 mg to about 25 mg); anti-inflammatory/analgesics, such as acetaminophen (preferably from about 60 mg to about 1000 mg, more preferably from about 300 mg to about 650 mg), ibuprofen (preferably from about 100 mg to about 800 mg, more preferably from about 200 mg to about 400 mg) and its salts sodium), aspirin (preferably from about 75 mg to about 1000 mg, more preferably from about 300 mg to about 650 mg) and its salts sodium), and naproxen (preferably from about 75 mg to about 500 mg, more preferably from about 125 mg to about 300 mg) and its salts sodium).

The subject invention also includes methods for treating or preventing cough in humans or lower animals by orally adminii. WO 92/07559 PCT/US91/07773 11 stering a composition disclosed hereinabove. In the methods of the subject invention, the daily dosage of dextromethorphan is preferably from about 0.1 mg/kg to about 10 mg/kg of body weight, more preferably from about 0.5 mg/kg to about 5 mg/kg, more preferably still from about 1 mg/kg to about 3 mg/kg. In the methods of the subject invention, it is preferred that a dextromethorphan composition be orally administered to a patient from about 1 to about 10 times daily, more preferably from about 2 to about 8 times daily, more preferably still from about 3 to about 6 times daily.

EXAMPLES

The following non-limiting examples are provided in order to illustrate the compositions and methods of the subject invention.

The liquid and lozenge compositions are made by conventional processes.

EXAMPLE I Liquid Cough Composition Ingredients Amount/15 ml Dose Dextromethorphan HBr 30.0 mg Propylene Glycol 1.74 g Ethanol 1.5 ml Menthol, Natural 12.5 mg Eucalyptus Oil 7.55 mg Flavorants 0.05 ml Sucrose 7.65 g Carboxymethylcellulose (CMC) 7.5 mg Microcrystalline Cellulose and Sodium CMC (Avicele RC591, FMC) Polysorbate 80 Glycerin Sorbitol F, D C Red #40 Glycine Sodium Hydroxide Water, Purified 187.5 300.0 300.0 28.2 7.8 q.s.

41 ~l WO 92/07559 PCT/US1/07773 12 A typical manufacturing process for making the above liquid cough composition is to prepare separate liquid phases by mixing together the following ingredients: dextromethorphan HBr, propylene glycol, ethanol, menthol, eucalyptus oil and flavorants; sucrose, CMC, Avicel, polysorbate 80, glycerin, sorbitol, and part of the water; and colorant, glycine, sodium hydroxide and part of the water. The three liquid phases are then blended together with the remainder of the water to produce the liquid cough composition.

EXAMPLE II Liquid Cough Composition Ingredients Am Dextromethorphan HBr Propylene Glycol Ethanol (95%) Polyethylene Glycol (Carbowax 400) Flavorants F, D C Red #40 Sodium Phosphate Dibasic Sodium Saccharin Water, Purified ount/15 ml Dose 15.0 mg 777.0 mg 1.5 ml 750.0 mg 0.05 ml 5.1 mg 231.0 mg 22.5 mg q.s.

EXAMPLE III Liquid Cough Composition Ingredients Dextromethorphan HBr Propylene Glycol Ethanol (95%) Menthol, Natural Eucalyptus Oil Flavorants F, D C Red #40 Sodium Phosphate Dibasic Sodium Saccharin Sucrose Glycerine Amount/15 ml Dose 30.0 mg 1.74 g 1.5 ml 22.5 mg 7.5 mg 0.05 ml 5.1 mg 231.0 mg 30.0 mg 8.16 g 750.0 mg

_I_

WO 92/07559 PCT/US91/07773 13 Sodium Hydroxide 3 Water, Purified q EXAMPLE IV Liquid Cough Composition .0 mg .s.

Ingredients A Dextromethorphan HBr Sucrose Carboxymethylcellulose (CMC) Microcrystalline Cellulose and Sodium CMC (Avicel® RC591, FMC) Polysorbate 80 Glycerin Sorbitol F, D C Red #40 Sodium Phosphate Dibasic Sodium Hydroxide Sodium Saccharin Propylene Glycol Ethanol (95%) Menthol Eucalyptus Oil Flavorants Water, Purified mount/15 ml Dose 30.0 mg 8.16 g 7.5 mg 187.5 mg 300.0 300.0 231.0 3.6 30.0 1.74 22.5 0.05 q.s.

I

d EXAMPLE V Liquid Cough Composition Ingredients Am( Dextromethorphan HBr Sucrose

CMC

Microcrystalline Cellulose and Sodium CMC (Avicel@ RC591, FMC) Polysorbate 80 Glycerin Sorbitol F, D C Red #40 Sodium Phosphate Dibasic ount/15 ml Dose 20.0 mg 8.16 g 7.5 mg 187.5 mg 300.0 300.0 231.0 L- ~i I 1 WO 92/07559 PC/US91/07773 14 Sodium Hydroxide Sodium Saccharin Propylene Glycol Phenol Ethanol (95%) Menthol Eucalyptus Oil Flavorants Water, Purified 30.0 1.74 100.0 22.5 0.05 q.s.

EXAMPLE VI Liquid Cough Composition Ingredients Am Dextromethorphan HBr Propylene Glycol Ethanol (95%) Sucrose

CMC

Microcrystalline Cellulose and Sodium CMC (Avicel® RC591, FMC) Polysorbate 80 Glycerin Flavorants F, D C Red #40 Sodium Phosphate Dibasic Sodium Hydroxide Sodium Saccharin Water, Purified ount/15 ml Dose 30.0 mg 777.0 mg 1.5 ml 8.16 g 7.5 mg 187.5 mg

A

300.0 0.05 5.1 231.0 3.6 22.5 q.s.

EXAMPLE VII Liquid Cough Composition Ingredients Dextromethorphan HBr Propylene Glycol Ethanol (95%) Menthol, Natural Eucalyptus Oil Sucrose Amount/15 ml Dose 30.0 mg 1.74 g 1.5 ml 22.5 mg 7.5 mg 8.16 g ri WO 92/07559 PCT/US91/07773 15

CMC

Microcrystalline Cellulose and Sodium CMC (Avicel® RC591, FMC) Polysorbate 80 Flavorants F, D C Red #40 Sodium Phosphate Dibasic Sodium Saccharin Glycerin Sodium Hydroxide Water, Purified 187.5 0.05 5.1 231.0 30.0 300.0 3.6 q.s.

EXAMPLE VIII Liauid Couah Comosition Inqredients Dextromethorphan HBr Sucrose Glycerin Sorbitol F, D C Red #40 Sodium Phosphate Dibasic Sodium Hydroxide Sodium Saccharin Propylene Glycol Ethanol (95%) Menthol Eucalyptus Oil Flavorants Water, Purified Amount/15 ml Dose 25.0 mg 8.16 g 300.0 mg 300.0 mg 3.0 mg 231.0 mg 3.6 mg 30.0 mg 1.74 g 1.5 ml 22.5 mg 7.5 mg 0.05 ml q.s.

EXAMPLE IX linuid Couah Comoosition Ingredients Dextromethorphan HBr Sucrose Glycerin Amount/15 ml Dose 30.0 mg 8.16 g 300.0 mg L__1 i. WO 92/07559 PCT/US91/07773 16 Sorbitol F, D C Red #40 Sodium Phosphate Dibasic Sodium Hydroxide Sodium Saccharin Propylene Glycol Phenol Ethanol (95%) Menthol Eucalyptus Oil Flavorants Water, Purified 300.0 231.0 3.6 30.0 1.74 100.0 22.5 0.05 q.s.

EXAMPLE X Compressed Tablet Composition Ingredients Amount/2.25 9 Lozenqe Dextromethorphan Base 5.0 mg Benzocaine 1.25 mg Talc 90.0 mg Flavorants 15.8 mg Caramel B&C #40 69.4 mg Trisodium Phosphate Dodecahydrate 40.0 mg Magnesium Stearate 45.0 mg Saccharin 15.0 mg Emdex q.s.

EXAMPLE XI Liquid Spray Cough Composition Ingredients Amount/3.5 ml Dose Dextromethorphan Base 25.0 mg Propylene Glycol 0.7 ml Ethanol 1.05 ml Polyethylene Glycol (Carbowax 400) 0.7 ml Sodium Saccharin 5.25 mg Flavorants 0.012 ml F, D C Red #40 1.19 mg Phenol 75.0 mg Purified Water q.s.

t WO 92/07559 PCT/US91/07773 -17 EXAMPLE XII Liquid Spray Cough Composition Ingredients Amount/3.5 ml Dose Dextromethorphan Base 10.0 mg Propylene Glycol 0.7 ml Ethanol 0.7 ml Polyethylene Glycol (Carbowax 400) 0.7 ml Monobasic Sodium Phosphate 8.4 mg Sodium Sacharin 7.0 mg Flavorants 0.14 ml F, D C Red #40 1.19 mg Purified Water q.s.

The liquid of Example XII is made by adding the dextromethorphan base to the propylene glycol with stirring. The polyethylene glycol, alcohol, flavorants, and sodium saccharin are added incrementally with stirring. The monobasic sodium phosphate is added as a 10% solution in purified water with stirring. The dye is added as a water solution with stirring.

Purified water is added to volume with stirring.

While particular embodiments of the subject invention have been described it will be obvious to those skilled in the art that various changes and modifications of the subject invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.

WHAT IS CLAIMED IS: A 1 'I

Claims (14)

1. An antitussive composition, in dosage unit form, when used for peroral administration wherein it comprises a safe and effective amount of dextromethorphan and an orally-acceptable pharmaceutical carrier, the composition being at a pH of 8 to 11.

2. An antitussive composition according to claim 1 wherein the composition pH is from 8.4 to

3. An antitussive composition, in dosage unit form, when used for peroral administration wherein it comprises a safe and effective amount of dextromethorphan; a safe and effective amount of another cough/cold drug active other than phenol, and an orally-acceptable pharmaceutical carrier; the composition having a pH of from 8 to 11.

4. An antitussive composition according to claim 3 wherein the cough/cold S drug active other than phenol is selected from the group consisting of an antihistamine, a bronchodilator, a decongestant, an expectorant, a local anaesthetic, or an anti-inflammatory/analgesic. An antitussive composition according to either claim 3 or 4 wherein the composition pH is from 8.4 to

6. An antitussive composition in dosage unit form, when used for peroral administration wherein it comprises a safe and effective amount of dextromethorphan; a safe and effective amount, of phenol; and an orally- acceptable pharmaceutical carrier; the composition having a pH of from greater than 9 to 11.

7. An antitussive composition according to claim 6 wherein the safe and effective amount of phenol is from 20 mg to 50 mg per dose. V 8. An antitussive composition according to either claim 6 or 7 wherein the composition pH is from greater than 9 to

9. A composition according to any one of claims 1-8 wherein the composition has a basic buffer strength of at I east 0.01, mEq base per dose, and from 1 mg to 50 mg, dextromethorphan per dose. A composition according to claim 9 wherein the composition has a basic buffer strength of from 0.05 to 2.5 mEq base per dose. III-

11. A composition according to either claim 9 or 10 wherein the composition has from 2.5 mg to 30 mg dextromethorphan per dose.

12. A composition according to any one of claims 1-11 wherein the composition is an aqueous-based liquid.

13. A composition according to claim 12 which also comprises from 0.5% to 3% Avicel® RC591.

14. A composition according to any one of claims 1-13 wherein the composition also comprises another cough/cold drug active selected from 1 mg to 8 mg chlorpheniramine per dose, from 6 mg to 50 mg diphenhydramine per dose, from 1 mg to 8 mg brompheniramine per dose, from 2 mg to 20 mg doxylamine per dose, from 0.5 mg to 4 mg triprolidine, from 5 mg to 50 mg ephedrine per dose, from 10 mg to 100 mg pseudoephedrine per dose, from 2 mg to 20 mg phenylephrine per dose, from 5 mg to 50 mg phenyl-propanolamine per dose, from 50 mg to 400 mg guaifenesin per dose, from 1 mg to 25 mg benzocaine per dose, from 1 mg to 10 mg dyclonine per dose, from 2 mg to 20 mg lidocaine per dose, from 5 mg to 50 mg butacaine per dose, from 50 mg to 750 mg benzyl alcohol per dose, from 0.1 mg to 4 mg dibucaine per dose, from 0.1 mg to 4 mg tetracaine per dose, from 10 mg to 150 mg phenolate sodium per dose, from mg to 200 mg salicyl alcohol per dose, from 1 mg to 10 mg hexylresorcinol per dose, from 2 mg to 50 mg menthol per dose, from 60 mg to 1000 mg acetaminophen per dose, from 100 mg to 800 mg ibuprofen per dose, from 75 mg to 1000 mg aspirin per dose, from 75 mg to 500 mg naproxen per dose, and mixtures thereof. S 25 DATED: 21 August, 1995 THE PROCTER GAMBLE COMPANY By their Patent Attorneys PHILLIPS ORMONDE FITZPATRICK A. e &I A& CiX S i- I.IH si_ I INTERNATIONAL SEARCH REPORT International Application No PCT/US 91/07773 I I. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, indicate all) 6 4 it Vi According to International Patent Classification (1PC) or to both National Classification and IPC A 61 K 31/05 A 61 K 31/485 A 61 K 9/00 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols A 61 K Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in the Fields Searched 8 III. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category Citation of Document, 1 with indication, where appropriate, of the relevant passages 12 Relevant to Claim No.13 A EP,A,0315332 (RICHARDSON-VICKS) 10 1-4,6,7 May 1989, see claims 1-2,7-8; page 4, lines (cited in the application) A US,A,4454140 GOLDBERG) 12 June 1,2,4,5 1984, see claims; column 3, lines 52-59 ,7 A US,A,4427681 MUNSHI) 24 1,2,4-7 January 1984, see claims 1,7,9,12-16 (cited in the application) A BE,A, 890008 (BRISTOL-MYERS) 18 3,4,6,7 February 1982, see claims 1,7-9,11,21-26; page 7, line 2 Special categories of cited documents :0 later document published after the international filing date or priority date and not in conflict with the application but document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international 7X document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publication date of another document of particular relevance; 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 such docu- other means ments, such combination being obvious to a person skilled 'P document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report

18-02-1992 20 03. 92 International Searching Authority Signatu horized Officer EUROPEAN PATENT OFFICEe Form ICT/ISA210 i.econd sheetl IJanuiar 19851 I international Application No Pa7,/e 91/07773 1 i. DOCUMENTS CONSIDERED TO BE REL-EVNT (CONTINUE FROM THE SECOND SHEET) Category0 Citaton of Doument, ith indication, where appropriate of the relevant passagesRlvn o li o Derwent Publications Limited, Database WPIL, accession number 90-075955, JP, A, 2056425 (RICHARDSON VICKS INC.) 26 February 1990, see the abstract 1,2,4,7 Fom PCT/ISA/2IO Jextira %beet) (Jantuary 1985) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. US 9107773 SA 53448 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 12/03/92 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 EP-A- 0315332 10-05-89 US-A- 4892877 09-01-90 AU-A- 2437288 27-04-89 JP-A- 1246221 02-10-89 US-A- 4454140 12-06-84 None US-A- 4427681 24-01-84 AU-A- 1748683 JP-A- 59074134

22-03-84

26-04-84 BE-A- 890008 18-02-82 US-A- 4294819 13-10-81 AT-B- 370624 25-04-83 AU-B- 549488 30-01-86 AU-A- 7368281 25-02-82 CA-A- 1144861 19-04-83 CA-A- 1156554 08-11-83 CH-A- 646331 30-11-84 DE-A- 3132518 27-05-82 FR-A,B 2488508 19-02-82 GB-A,B 2082456 10-03-82 JP-A- 57059804 10-04-82 LU-A- 83559 14-04-82 NL-A- 8103804 16-03-82 OA-A- 6883 30-04-83 SE-B- 451667 26-10-87 SE-A- 8104881 19-02-82 US-A- 4339428 13-07-82 4 I ir" w For more details about this annex see Official Journal of the European Patent Office, No. 12/82 c