IE913792A1 - Dextromethorphan antitussive compositions - Google Patents

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.

Description

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 IQ Dextromethorphan (racemethorphan), 3-methoxy-17-methylmorphinan, 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 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 2Q 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 SmithKHne Consumer, Contac Nighttime Cold Medicine by SmithKline Consumer, Contac Severe Cold Formula Caplets by SmithKline Consumer, Dlmacol Caplets by Robins, Dorcol 3q Children's Cough Syrup by Sandoz Consumer, Hold by SmithKline Beecham, Naldecon DX Adult Liquid by Bristol Laboratories, 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 - 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 Pharmaceu5 ticals, Snaplets-Multi by Baker Cummins Pharmaceuticals, St. Joseph Cough Suppressant for Children by Plough, St. Joseph 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 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 RichardsonVicks, Inc., Vicks Cough Silencers Cough Drops by RichardsonVicks, Inc., Vicks Daycare Daytime Colds Medicine Caplets by Richardson-Vicks, Inc., Vicks Daycare Multi-Symptom Colds Medi20 cine 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 Richardson30 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 Pharmaceuticals, 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, - 3 Poly-Histine DM Syrup by Bock, Quelidrine Syrup by Abbott, Rondec-DM Oral Drops by Ross, Rondec DM Syrup by Ross, TusibronDM 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, A.H., & E. G. Triggs, Buccal Absorption of Basic 10 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 compo15 sitions are held and circulated in the mouth for 5 minutes. Dextromethorphan is not disclosed as one of those drugs tested in Beckett and Triggs. The disclosure of Beckett and Triggs 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.

SUMMARY OF THE INVENTION It is an object of the subject invention to provide dextromethorphan compositions for peroral administration which will provide more rapid antitussive action than commercially available compositions. - 4 It is also an object of the subject invention to provide methods for achieving rapid antitussive action from dextromethorphan compositions.

The subject invention involves pharmaceutical compositions 5 for oral administration which consist essentially of a safe and effective amount of dextromethorphan and an orally-acceptable pharmaceutical carrier, the composition having a pH of from about to about 11.

The subject invention also involves pharmaceutical composi10 tions for oral administration which comprise a safe and effective amount of dextromethorphan, safe and effective amounts of 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.

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.

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 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 means racemethorphan, 3-methoxy-17-methylmorphinan (dl-cis1,3,4,9,10,10a-hexahydro-6-methoxy-l1-methyl-2H-10,4a-iminoethanophenanthrene: 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 5 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 9.5, 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 - 6 effective 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 10, also preferably from about 9.1 to about 9.5.

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 buffer systems useful in the compositions of the subject inven30 tion are phosphate buffer systems.

A preferred component of the carrier of the compositions of the subject invention is microcrystalline cellulose or a mixture of mycrocrystall ine cellulose and carboxymethyl cellulose sodium. Microcrystalline cellulose and mixtures of microcrystalline cellulose and carboxymethyl cellulose sodium are available from FMC Corporation under the trade name Avicel®. Such mixtures - 7 preferably have a ratio of microcrystalline cellulose to carboxymethyl cellulose 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 carboxymethyl cellulose 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 carboxymethyl cellulose 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 10 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 lbs/ft3 loose pack and about 52 lbs/ft3 tight pack. Its specific gravity is 1.55, ash content about 2%, 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 carboxymethyl cellulose sodium incorporated in the compositions of the subject invention is preferably from about 0.5% to about 3%, more preferably from about 1% to about 2%, more preferably still about 1.5%.

The compositions of the subject invention are intended for 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 - 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. (Artificial saliva formulation is disclosed in Fusayema, T., 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 glycol, glycerin and sorbitol; more pre15 ferred 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 carboxymethyl cellulose, sodium carboxymethyl cellulose, 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 80, 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 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 • 9 miscellaneous 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 composi10 tions 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) and its salts (e.g., maleate), diphenhydramine (preferably from about 6 mg to about 50 mg, more preferably from about 12 mg to about 25 mg) and its salts (e.g., 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 (e.g., 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 (e.g., 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 (e.g., 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 (e.g., hydrochloride), phenylephrine (preferably from about 2 mg to about 20 mg, more preferably from about 5 mg to about 10 mg) and its salts (e.g., hydrochloride), phenylpropanolamine (preferably from about 5 mg to about 50 mg, more preferably from about 12 mg to about 25 mg) and its salts (e.g., hydrochloride); expectorants, such as guaifenesin (preferably from about 50 mg to - ίο 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 15 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 (e.g., hydrochloride), lidocaine (preferably from about 2 mg to about 20 mg, more preferably from about 4 mg to about 10 mg) and its salts (e.g., 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 50 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 (e.g., 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 (e.g., hydrochloride), phenolate sodium (preferably from about 10 mg to about 150 mg, more preferably from about 20 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), hexyl resorcinol (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 (e.g., sodium), aspirin (preferably from about 75 mg to about 1000 mg, more preferably from about 300 mg to about 650 mg) and its salts (e.g., 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 (e.g., sodium).

The subject invention also includes methods for treating or preventing cough in humans or lower animals by orally adminiIE 913792 - 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.

EXAMPLE 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 20 Propylene Glycol 1.74 9 Ethanol (95%) 1.5 ml Menthol, Natural 12.5 mg Eucalyptus Oil 7.55 mg Flavorants 0.05 ml 25 Sucrose 7.65 g Carboxymethyl cellulose (CMC) Microcrystalline Cellulose and 7.5 mg Sodium CMC (Avicel® RC591, FMC) 187.5 mg Polysorbate 80 3.0 mg 30 Glycerin 300.0 mg Sorbitol 300.0 mg F, D & C Red #40 3.0 mg Glycine 28.2 mg Sodium Hydroxide 7.8 mg 35 Water, Purified q.s. - 12 A typical manufacturing process for making the above liquid cough composition is to prepare separate liquid phases by mixing together the following ingredients: (1) dextromethorphan HBr, propylene glycol, ethanol, menthol, eucalyptus oil and flavorants; (2) sucrose, CMC, Avicel, polysorbate 80, glycerin, sorbitol, and part of the water; and (3) 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 Liauid Couqh Composition Inqredients Amount/15 ml Dose Dextromethorphan HBr 15.0 mg Propylene Glycol 777.0 mg 15 Ethanol (95%) 1.5 ml Polyethylene Glycol (Carbowax 400) 750.0 mg Flavorants 0.05 ml F, D & C Red #40 5.1 mg Sodium Phosphate Dibasic 231.0 mg 20 Sodium Saccharin 22.5 mg Water, Purified q.s.

EXAMPLE III Liquid Cough Composition Inqredients Amount/15 ml Dose 25 Dextromethorphan HBr 30.0 mg Propylene Glycol 1.74 g Ethanol (95%) 1.5 ml Menthol, Natural 22.5 mg Eucalyptus Oil 7.5 mg 30 Flavorants 0.05 ml F, D & C Red #40 5.1 mg Sodium Phosphate Dibasic 231.0 mg Sodium Saccharin 30.0 mg Sucrose 8.16 g 35 Glycerine 750.0 mg Sodium Hydroxide Water, Purified EXAMPLE IV Liauid Cough Compos 3.0 q.s. ition mg 5 Ingredients Amount/15 ml Dose Dextromethorphan HBr 30.0 mg Sucrose 8.16 g Carboxymethylcellulose (CMC) 7.5 mg Microcrystalline Cellulose and 187.5 mg 10 Sodium CMC (Avicel® RC591, FMC) Polysorbate 80 3.0 mg Glycerin 300.0 mg Sorbitol 300.0 mg F, D & C Red #40 3.0 mg 15 Sodium Phosphate Dibasic 231.0 mg Sodium Hydroxide 3.6 mg Sodium Saccharin 30.0 mg Propylene Glycol 1.74 g Ethanol (95%) 1.5 ml 20 Menthol 22.5 mg Eucalyptus Oil 7.5 mg Flavorants 0.05 ml Water, Purified q.s.

EXAMPLE V Liquid Cough Composition Ingredients Amount/15 ml Dose Dextromethorphan HBr 20.0 mg Sucrose 8.16 g CMC 7.5 mg 30 Microcrystalline Cellulose and Sodium CMC (Avicel® RC591, FMC) 187.5 mg Polysorbate 80 3.0 mg Glycerin 300.0 mg Sorbitol 300.0 mg 35 F, D & C Red #40 3.0 mg Sodium Phosphate Dibasic 231.0 mg Sodium Hydroxide 5.0 mg Sodium Saccharin 30.0 mg Propylene Glycol 1.74 g Phenol 100.0 mg Ethanol (95%) 1.5 ml Menthol 22.5 mg Eucalyptus Oil 7.5 mg Flavorants 0.05 ml Water, Purified q.s.

EXAMPLE VI Liquid Cough Composition Inqredients Amount/15 ml Dose Dextromethorphan HBr 30.0 mg Propylene Glycol 777.0 mg Ethanol (95%) 1.5 ml Sucrose 8.16 g CMC 7.5 mg Microcrystalline Cellulose and 187.5 mg Sodium CMC (Avicel® RC591, FMC) Polysorbate 80 3.0 mg Glycerin 300.0 mg Flavorants 0.05 ml F, D & C Red #40 5.1 mg Sodium Phosphate Dibasic 231.0 mg Sodium Hydroxide 3.6 mg Sodium Saccharin 22.5 mg Water, Purified q.s. EXAMPLE VII Liauid Couah ComDosition Inaredients Amount/15 ml Dose Dextromethorphan HBr 30.0 mg Propylene Glycol 1.74 g Ethanol (95%) 1.5 ml Menthol, Natural 22.5 mg Eucalyptus Oil 7.5 mg Sucrose 8.16 g CMC 7.5 mg Microcrystalline Cellulose and 187.5 mg Sodium CMC (Avicel® RC591, FMC) Polysorbate 80 3.0 mg 5 Flavorants 0.05 ml F, D & C Red #40 5.1 mg Sodium Phosphate Dibasic 231.0 mg Sodium Saccharin 30.0 mg Glycerin 300.0 mg 10 Sodium Hydroxide 3.6 mg Water, Purified q.s. EXAMPLE VIII Liauid Couah ComDosition 15 Inaredients Amount/15 ι nl Dose Dextromethorphan HBr 25.0 mg Sucrose 8.16 9 Glycerin 300.0 mg Sorbitol 300.0 mg 20 F, D & C Red #40 3.0 mg Sodium Phosphate Dibasic 231.0 mg Sodium Hydroxide 3.6 mg Sodium Saccharin 30.0 mg Propylene Glycol 1.74 9 25 Ethanol (95%) 1.5 ml Menthol 22.5 mg Eucalyptus Oil 7.5 mg Flavorants 0.05 ml Water, Purified q.s. 30 EXAMPLE IX Liauid Couah ComDosition Inaredients Amount/15 ml Dose Dextromethorphan HBr 30.0 mg 35 Sucrose 8.16 9 Glycerin 300.0 mg Sorbitol 300.0 mg F, D & C Red #40 3.0 mg Sodium Phosphate Dibasic 231.0 mg Sodium Hydroxide 3.6 mg Sodium Saccharin 30.0 mg Propylene Glycol 1.74 9 Phenol 100.0 mg Ethanol (95%) 1.5 ml Menthol 22.5 mg Eucalyptus Oil 7.5 mg Flavorants 0.05 ml Water, Purified q.s.

EXAMPLE X Compressed Tablet Composition Ingredients Amount/2.25 g Lozenge 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 Liguid Spray Cough Composition Ingredients Amount/3.5 ml Dose Dextromethorphan Base 25.0 mg Propylene Glycol 0.7 ml Ethanol (95%) 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. - 17 EXAMPLE XII Liquid Spray Cough Composition Inqredients Amount/3.5 ml Dose Dextromethorphan Base 10.0 mg Propylene Glycol 0.7 ml Ethanol (95%) 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.

Claims (9)

1. An antitussive composition, in dosage unit form, for peroral administration characterized in that it consists essentially of a safe and effective amount of dextromethorphan and an orally-acceptable pharmaceutical carrier, the composition 5 being at a pH of 8 to 11, preferably from 8.4 to 10.

2. An antitussive composition, in dosage unit form, for peroral administration characterized in that it comprises a safe and effective amount of dextromethorphan; a safe and effective 10 amount of another cough/cold drug active other than phenol, preferably an antihistimine, a brochodilator, a decongestant, an expectorant, a local anesthetic, or an anti-inflammatory/ analgesic; and an orally-acceptable pharmaceutical carrier; the composition having a pH of from 8 to 11, preferably from 8.4 to 15 10 ·

3. An antitussive composition in dosage unit form, for peroral administration characterized in that it comprises a safe and effective amount of dextromethorphan; a safe and effective 2Q amount, preferably from 20 mg to 50 mg, per dose of phenol; and an orally-acceptable pharmaceutical carrier; the composition having a pH of from greater than 9 to 11, preferably from greater than 9 to 10. 25

4. The composition of any of Claims 1-3 wherein the composition has a basic buffer strength of at least 0.01, preferably from 0.05 to 2.5, mEq base per dose, and from 1 mg to 50 mg, preferably from 2.5 mg to 30 mg, dextromethorphan per dose.

5. The composition of any of Claims 1-4 wherein the composition is an aqueous-based liquid, which preferably also comprises from 0.5% to 3% Avicel® RC591. 6 * * *

6. The composition of any of Claims 1-5 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 phenyl5 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 10 0.1 mg to 4 mg tetracaine per dose, from 10 mg to 150 mg phenolate sodium per dose, from 20 mg to 200 mg salicyl alcohol per dose, from 1 mg to 10 mg hexyl resorcinol 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 15 1000 mg aspirin per dose, from 75 mg to 500 mg naproxen per dose, and mixtures thereof.

7. The use of dextromethorphan for the manufacture of a composition of any of Claims 1-6 for the treatment or prevention 20 of cough in humans by peroral administration of the composition to the human.

8. An antitussive composition according to any one of Claims 1-3, substantially as hereinbefore described and exemplified.

9. Use according to Claim 7, substantially as hereinbefore described and exemplified.