United States Patent c191
`Smith
`
`[54] DEXTROMETHORPHAN ANTITUSSIVE
`COMPOSmONS
`
`[75]
`
`Inventor: Ronald L. Smith, West Chester, Ohio
`
`[73] Assignee: The Procter 4 Gamble Company,
`Cincinnati, Ohio
`
`[21] Appl. No.: 841.244
`
`[22] Filed:
`
`Feb.24, 1992
`
`Related U.S. Application Data
`[63] Continuation of Ser. No. 606,294, Oct. 31, 1990, aban(cid:173)
`doned.
`Int. a.~ .............................................. A61K 31/44
`[51]
`[52] U.S. a ..................................................... 514/289
`[58] Field of Search ........... : ............................. 514/289
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`4,427,681 1/1984 Munshi ................................ 424/260
`4,454,140 6/1984 Goldberg et al. ................... 424/260
`4,892,877 1/1990 Sorrentino .......................... 514/289
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll lllll lllll lllll llllll Ill lllll llll
`US005196436A
`S,196,436
`[11] Patent Number:
`[45] Date of Patent: Mar. 23, 1993
`
`OTHER PUBLICATIONS
`Chem. Abstr-100 109144J (1984).
`Chem. Abst.-106-72813k (1987).
`Merck Index, 10th Edition (1983), M. Windholz ed.,
`No. 8009, p. 1170.
`Physician's Desk Reference for Nonprescription Drugs,
`11th Edition (1990), E. R. Barnhardt, pub., p. 306.
`Physician's Desk Reference, 44th Edition (1990), E. R.
`Barnhardt, publ. p. 309.
`Beckett, A.H. and 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.
`Primary Examiner-S. J. Friedman
`Attorney, Agent, or Firm-M. B. Graff, IV; J. J. Yetter;
`T. H. O'Flaberty
`[57]
`ABSTRACT
`The subject invention involves antitussive pharmaceuti(cid:173)
`cal compositions for the peroral administration of dex(cid:173)
`tromethorphan, the composition being at a pH of from
`about 8 to about 11.
`
`8 Oaims, No Drawings
`
`Exhibit 1153
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`1
`
`DEXTROMETHORPHAN ANTITUSSIVE
`COMPOSmONS
`
`5,196,436
`
`2
`Cough Silencers Cough Drops by Richardson-Vicks,
`Inc., Vicks Daycare Daytime Colds Medicine Caplets
`by Richardson-Vicks, Inc., Vicks Daycare Multi-Symp-
`tom Colds Medicine Liquid by Richardson-Vicks, Inc.,
`Vicks Formula 44 Cough Control Discs by Richardson(cid:173)
`Vicks, Inc., Vicks Formula 44 Cough Medicine by
`Richardson-Vicks, Inc., Vicks Formula 44D Deconges(cid:173)
`tant 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 Medi(cid:173)
`cine by Richardson-Vicks, Inc., Vicks Pediatric For(cid:173)
`mula 44 Cough & Colds Medicine by Richardson-
`15 Vicks, Inc., Vicks Pediatric Formula 44 Cough & Con(cid:173)
`gestion Medicine by Richardson-Vicks, Inc., Ambenyl(cid:173)
`D Decongestant Cough Formula by Forest Pharmaceu(cid:173)
`ticals, 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-Mcthorphan Hydrobro-
`mide Syrup by Lcderle, Humibid DM Tablets by
`Adams, loTuss-DM Liquid by Muro, Medi-Tuss DM
`by Warner Chilcott, Phenergan with Dextromcthor(cid:173)
`phan by Wyeth-Ayerst, Poly-Histine DM Syrup by
`Bock, Quelidrine Syrup by Abbott, Rondec-DM Oral
`Drops by Ross, Randee DM Syrup by Ross, Tusibron(cid:173)
`DM by RAM Laboratories, Tussar DM by Rorer Phar(cid:173)
`maceuticals, and Tussi-Organidin DM Liquid by
`Wallace. Delsym Cough Suppressant Syrup by McNeil
`Consumer contains dextromethorphan polistircx 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 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 in(cid:173)
`creased 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 Triggs. The disclo(cid:173)
`sure of Beckett and Tn"ggs 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 arc al(cid:173)
`lowed to dissolve in the mouth where the dissolution
`liquid is rapidly swallowed.
`U.S. Pat. No. 4,892,877 issued to Sorrentino on Jan. 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. Pat. No.
`4,427,681 issued to Munshi on Jan. 24, 1984, discloses
`thixotropic compositions for the treatment of coughs
`comprising both dextromethorphan and A vicel ® RC-
`591. These patents are hereby incorporated by refer-
`ence.
`
`This is a continuation of application Ser. No. S
`07/606,294, filed on Oct. 31, 1990, now abandoned.
`
`TECHNICAL FIELD
`This invention is concerned with novel antitussive
`compositions containing dcxtromcthorphan. More par- 10
`ticularly, it is concerned with compositions and meth(cid:173)
`ods for rapidly achieving therapeutic systemic levels of
`dcxtromcthorphan.
`
`BACKGROUND OF THE INVENTION
`Dcxtromethorphan (raccmethorphan), 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 20
`as an antitussive agent in commercial products as dis(cid:173)
`closed in the Physician's Desk Reference for Nonprescrip(cid:173)
`tion Drugs, 1 lth 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 2S
`Cough Syrup by Glenbrook, Benylin DM by Parke(cid:173)
`Davis, Benylin Expectorant by Parke-Davis, Cerose(cid:173)
`DM by Wyeth-Ayerst, Cheracol D Cough Formula by
`Upjohn, Cheracol Plus Head Cough/Cold Formula by
`Upjohn, Cough Formula Comtrex by Bristol-Myers 30
`Products, Comtrex Multi-Symptom Cold Reliever Ta(cid:173)
`blets/Caplets/Liquid/Liquigels by Bristol-Myers Prod(cid:173)
`ucts, Contac Cough Formula by SmithKline Consumer,
`Contac Cough & Sore Throat Formula by SmithKiline
`Consumer, Contac Jr. Children's Cold Medicine by 35
`SmithKline Consumer, Contac Nighttime Cold Medi(cid:173)
`cine 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, 40
`Naldecon DX Adult Liquid by Bristol Laboratories,
`Naldecon DX Children's Syrup by Bristol Laborato(cid:173)
`ries, Naldecon DX Pediatric Drops by Bristol Labora(cid:173)
`tories, Naldecon Senior DX Cough/Cold Liquid by
`Bristol Laboratories, Novahistine DMX by Lakeside 4S
`Pharmaceuticals, Pediacare Cough-Cold Formula Liq(cid:173)
`uid and Chewable Tablets by McNeil Consumer Prod(cid:173)
`ucts, Pediacare Night Rest Cough-Cold Formula Liq(cid:173)
`uid by McNeil Consumer Products, Robitussin Night
`Relief by Robins, Robitussin-CF by Robins, Robitussin- so
`DM by Robins, Scot-Tussin Sugar-Free DM Cough &
`Cold Medicine by Scot-Tussin, Snaplets-DM by Baker
`Cummins Pharmaceuticals, Snaplets-Multi by Baker
`Cummins Pharmaceuticals, St. Joseph Cough Suppres(cid:173)
`sant for Children by Plough, St. Joseph Nighttime Cold SS
`Medicine by Plough, Sucrets Cough Control Formula
`by SmithKline Beecham, Sudafed Cough Syrup by
`Burroughs Wellcome, Triaminic Night Light by San(cid:173)
`doz Consumer, Triaminic-DM Syrup by Sandoz Con(cid:173)
`sumer, Triaminicol Multi-Symptom Cold Tablets by 60
`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 Prod(cid:173)
`ucts, Tylenol Cold Medication No Drowsiness Formula 6S
`Caplets by McNeil Consumer Products, Vicks Chil(cid:173)
`dren's Cough Syrup by Richardson-Vicks, Inc., Vicks
`Children's NyQuil by Richardson-Vicks, Inc., Vicks
`
`SUMMARY OF THE INVENTION
`It is an object of the subject invention to provide
`dextromethorphan compositions for peroral administra(cid:173)
`tion which will provide more rapid antitussivc action
`than commercially available compositions.
`It is also an object of the subject invention to provide
`methods for achieving rapid antitussive action from
`dextromethorphan compositions.
`
`000002
`
`

`

`5,196,436
`
`3
`The subject invention involves pharmaceutical com(cid:173)
`positions for oral administration which consist essen(cid:173)
`tially of a safe and effective amount of dextromethor(cid:173)
`phan 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 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-accepta(cid:173)
`ble 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 inven(cid:173)
`tion comprise a safe and effective amount of dextro(cid:173)
`methorphan, and possibly other drug actives. The 25
`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 30
`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 35
`therapy and like factors.
`Dextromethorphan is known to have .pharmacologi(cid:173)
`cal activity as an antitussive agent. As used herein,
`"dextromethorphan"
`means
`racemethorphan, 3-
`methoxy-17-methylmorphinan
`(dl-cis-1,3,4,9, 10, 1 Oa- 40
`hexahydro-6-methoxy-11-methyl-2H-l 0,4a-iminoe(cid:173)
`thanophenanthrene:
`
`4
`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 con(cid:173)
`sist essentially of a safe and effective amount of dextro-
`S methorphan, 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
`10 the subject invention comprise a safe and effective
`ll!ld effective
`amount of dextromethorphan, safe
`amounts of other cough/cold drug actives other than
`phenol, and an orally-acceptable pharmaceutical car(cid:173)
`rier, the composition having a pH of from about 8 to
`15 about 11, preferably from about 8.4 to about 10, more
`preferably still from about 8.5 to about 9.5, most prefer(cid:173)
`ably about 9. Other preferred compositions of the sub(cid:173)
`ject invention comprise a safe and effective amount of
`dextromethorphan, a safe and effective amount of phe-
`20 nol, 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, com(cid:173)
`pared 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 millie(cid:173)
`quivalents (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
`45 pharmaceutically-acceptable carrier preferably com(cid:173)
`prising a pharmaceutically-acceptable buffer system.
`Examples of pharmaceutically-acceptable buffer sys(cid:173)
`tems useful in the compositions of the subject invention
`include, but are not limited to, phosphate buffer systems
`so which are a mixture of salts of monohydrogen and dihy(cid:173)
`drogen phosphate, sodium hydroxide/glycine buffer
`systems, and carbonate and hydrogen carbonate buffer
`systems. Preferred buffer systems useful in the composi-
`tions of the subject invention are phosphate buffer sys(cid:173)
`tems.
`A preferred component of the carrier of the composi(cid:173)
`tions of the subject invention is microcrystalline cellu(cid:173)
`lose or a mixture of mycrocrystalline cellulose and car(cid:173)
`boxymethylcellulose sodium. Microcrystalline cellulose
`and mixtures of microcrystalline cellulose and carboxy(cid:173)
`methylcellulose sodium are available from FMC Cor-
`poration under the trade name A vicel @. Such mixtures
`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
`
`and pharmaceutically-acceptable salts thereof. Pre(cid:173)
`ferred salts of dextromethorphan include the hydrobro- 55
`mide salt.
`The compositions of the subject invention preferably
`comprise from about 1 mg to about 50 mg dextrometh(cid:173)
`orphan per dose, more preferably from about 2.5 mg to
`about 30 mg dextromethorphan per dose. Liquid com- 60
`positions 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% dextrometh(cid:173)
`orphan. A typical dose for a liquid antitussive composi- 65
`tion 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
`
`000003
`
`

`

`25
`
`5
`commercially available microcrystallinc cellulose mar(cid:173)
`keted by FMC Corporation, Food and Pharmaceutical
`Products Division, Philadelphia, Pa. A vicel ® RC591
`is said to be a colloidal form of about 89% microcrystal(cid:173)
`linc cellulose gel blended with about 11 % sodium car- S
`boxymcthylcellulose which is dried; the product is eas-
`ily 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 arc as
`follows: loss on drying: less than 6% at time of ship- 10
`mcnt; heavy metals: less than 10 parts per million; vis(cid:173)
`cosity 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. A vcragc particle size is
`about 28 microns. Its bulk density is about 37 lbs/ft3 IS
`loose pack and about 52 lbs/ft3 tight pack. Its specific
`gravity is 1.55, ash content about 2%, pH of a 2% dis(cid:173)
`persion in water is 6 to 8. The product is described more
`fully in FMC Corporation bulletin L-318 "Avicel ®
`RC-CL Microcrystallinc Cellulose" which is inccrpo- 20
`rated herein by reference.
`The quantity of microcrystallinc cellulose or mixture
`of microcrystallinc cellulose and carboxymethylccllu(cid:173)
`lose 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 in(cid:173)
`tended for peroral administration. Examples of such 30
`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 35
`lozenges, powders, and chewable tablets. The pH of
`such solid dosage forms 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 40
`formulation is disclosed in Fusayema, T., T. Katayori &
`S. Nomoto, "Artificial Saliva", Journal of Dental Re(cid:173)
`search, Vol. 42 (1963), pp. 1183-1197, which is incorpo(cid:173)
`rated herein by reference).
`Dextromethorphan is relatively insoluble in water at 4S
`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 pro(cid:173)
`vide for dissolution of the dextromethorphan in the
`composition and in the oral cavity. Preferred cosolvents so
`for this purpose include ethanol, propylene glycol,
`polyethylene glycol, glycerin and sorbitol; more pre(cid:173)
`ferred cosolvcnts include ethanol, propylene glycol and
`glycerin.
`For the liquid compositions of the subject invention, SS
`the carrier preferably includes some of the following
`optional ingredients: water; sweetening agents, such as
`sucrose, com syrup, invert sugar, dextrose, sodium
`saccharin, aspartame, sorbitol, honey, and magnasweet;
`aromatic ingredients, such as menthol, anethol, cam- 60
`phor, thymol, methyl salicylatc, eucalyptus oil and pep(cid:173)
`permint oil; other flavoring agents; thickening agents,
`such as carboxymethylcellulose, sodium carboxy(cid:173)
`methylcellulose, cellulose, glycerine and polyethylene
`glycol; coloring agents; preservatives, such as sodium 65
`benzoate and cetylpyridinium chloride; miscellaneous
`ingredients, such as potassium sorbatc, sodium chloride,
`titanium dioxide, polysorbate 80, sodium citrate, sodium
`
`5,196,436
`
`6
`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 hcrcinabovc for the liquid compo(cid:173)
`sitions, and additionally the following optional ingredi(cid:173)
`ents may be included in such compositions: solid dilu(cid:173)
`ents, binders, disintcgrants and opacificrs, such as sili(cid:173)
`con dioxide, talc, povidone, Kaolin, dicalcium phos(cid:173)
`phate, calcium sulfate, lactose and starch; and miscella(cid:173)
`neous ingredients, such as acacia, capsicum, mannitol,
`sodium alginate, alginic acid, veegum, guar gum, gela(cid:173)
`tin, cthylccllulose, magnesium stcaratc; bcntonite 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 arc pre(cid:173)
`ferred. Cough/cold drug actives useful in the composi(cid:173)
`tions of the subject invention include antihistamines,
`bronchodilators, decongestants, expectorants, local an(cid:173)
`esthetics 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 I mg to about
`8 mg, more preferably from about 2 mg to about 4 mg)
`and its salts (e.g., maleate), diphcnhydramine (prefera(cid:173)
`bly 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 I mg to about 8 mg, more preferably from about
`2 mg to about 4 mg) and its salts, doxylaminc (prefera(cid:173)
`bly from about 2 mg to about 20 mg, more preferably
`from about 6 mg to about 12 mg) and its salts (e.g.,
`succinate), triprolidinc (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); bronchodila(cid:173)
`tors, such as ephedrine (preferably from about S mg to
`about 50 mg, more preferably from about 10 mg to
`about 25 mg) and its salts (e.9., 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 S mg to
`about 10 mg) and its salts (e.g., hydrochloride), phenyl(cid:173)
`propanolamine (preferably from about S 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 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), dycloninc (preferably
`from about 1 mg to about 10 mg, more preferably from
`about 2 mg to about 4 mg) and its salts (e.g., hydrochlo(cid:173)
`ride), 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 S 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
`SO mg to about 750 mg, more preferably from about 100
`mg to about 500 mg), dibucaine (preferably from about
`
`000004
`
`

`

`5,196,436
`
`8
`sucrose, CMC, A vice!, polysorbate 80, glycerin, sorbi(cid:173)
`tol, 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 remain(cid:173)
`der of the water to produce the liquid cough composi(cid:173)
`tion.
`
`Ingredients
`
`EXAMPLE II
`Liquid Cough Composition
`Amount/IS ml Dose
`IS.O mg
`. 777.0 mg
`l.S ml
`750.0 mg
`o.os ml
`S.I mg
`231.0 mg
`22.S mg
`q.s.
`
`Dcxtromethorphan HBr
`Propylene Glycol
`Ethanol (9S%)
`Polyethylene Glycol (Carbowax 400)
`Flavorants
`F, D & C Reel #40
`Sodium Phosphate Dibasic
`Sodium Saccharin
`Water, Purified
`
`Ingredients
`
`EXAMPLE III
`Liquid Cough Composition
`Amount/IS ml Dose
`
`Dcxtromethorphan HBr
`Propylene Glycol
`Ethanol (9S%)
`Menthol, Natural
`Eucalyptus Oil
`Flavorants
`F, D & C Reel #40
`Sodium Phosphate Dibasic
`Sodium Saccharin
`Sucrose
`Glycerine
`Sodium Hydroxide
`Water, Purified
`
`30.0 mg
`1.74 g
`l.S ml
`22.S mg
`1.S mg
`o.os ml
`5.1 mg
`231.0 mg
`30.0 mg
`8.16 g
`750.0 mg
`3.0 mg
`q.s.
`
`Ingredients
`
`EXAMPLE IV
`Liguid Cough Composition
`Amount/IS ml Dose
`
`7
`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 (prefer- s
`ably from about 10 mg to about 150 mg, more prefera(cid:173)
`bly 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), hexylre(cid:173)
`sorcinol (preferably from about 1 mg to about 10 mg, 10
`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 lS
`preferably from about 300 mg to about 650 mg), ibu(cid:173)
`profen (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 )000 mg, more preferably from 20
`about 300 mg to about 650 mg) and its salts (e.g., so(cid:173)
`dium), 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 treat- 2s
`ing or preventing cough in humans or lower animals by
`orally administering a composition disclosed herein(cid:173)
`above. 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 30
`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 35
`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 40
`order to illustrate the compositions and methods of the
`subject invention. The liquid and lozenge compositions
`are made by conventional processes.
`
`EXAMPLEV
`Liquid Cough Composition
`Amount/IS ml Dose
`
`30.0 mg
`8.16 g
`1.S mg
`187.S mg
`
`3.0 mg
`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
`o.os ml
`q.s.
`
`20.0 mg
`8.16 g
`1.S mg
`187.5 mg
`
`3.0 mg
`300.0 mg
`300.0 mg
`3.0 mg
`231.0 mg
`5.0 mg
`30.0 mg
`1.74 g
`100.0 mg
`1.5 ml
`22.S mg
`1.S mg
`
`Dcxtromethorphan HBr
`Sucrose
`Carboxymethylcellulose (CMC)
`Microcrystalline Cellulose and
`Sodium CMC (Avicel @ RCS91, FMC)
`Polysorbate 80
`Glycerin
`Sorbitol
`F, D & C Reel #40
`Sodium Phosphate Dibasic
`- - - - - - - - - - - - - - - - - - - - - 45 Sodium Hydroxide
`Sodium Saccharin
`EXAMPLE I
`Propylene Glycol
`Liquid Cough Composition
`Ethanol (95%)
`Amount/IS ml Dose
`Menthol
`30.0 mg
`Eucalyptus
`1.74 g
`SO Flavorants
`l.S ml
`Water, Purified
`12.S mg
`1.SS mg
`o.os ml
`1.6S g
`1.S mg
`187.S mg
`
`Ingredients
`
`Dcxtromethorphan HBr
`Propylene Glycol
`Ethanol (9S%)
`Menthol, Natural
`Eucalyptus Oil
`Flavorants
`Sucrose
`Carboxymethylcellulose (CMC)
`Microcrystalline Cellulose and
`Sodium CMC (Avicel@ RC591, FMC)
`Polysorbate 80
`Glycerin
`Sorbitol
`F, D & C Reel #40
`Glycine
`Sodium Hydroxide
`Water, Purified
`
`3.0 mg
`300.0 mg
`300.0 mg
`3.0 mg
`28.2 mg
`7.8 mg
`q.s.
`
`A typical manufacturing process for making the
`above liquid cough composition is to prepare separate 6S
`liquid phases by mixing together the following ingredi(cid:173)
`ents: (1) dextromethorphan HBr, propylene glycol,
`ethanol, menthol, eucalyptus oil and flavorants; (2)
`
`Ingredients
`SS Dcxtromethorphan HBr
`Sucrose
`CMC
`Microcrystalline Cellulose and
`Sodium CMC (Avicel@ RCS91, FMC)
`Polysorbate 80
`60 Glycerin
`Sorbitol
`F, D & C Reel #40
`Sodium Phosphate Dibasic
`Sodium Hydroxide
`Sodium Saccharin
`Propylene Glycol
`Phenol
`Ethanol (95%)
`Menthol
`Eucalyptus Oil
`
`000005
`
`

`

`9
`-continued
`
`5,196,436
`
`10
`-continued
`
`Flavorants
`Water, Purified
`
`Ingredients
`
`0.05 ml
`q.s.
`
`EXAMPLE VI
`Liquid Cough Composition
`Amount/15 ml Dose
`
`Dextromethorpban HBr
`Propylene Glycol
`Ethanol (95%)
`Sucrose
`CMC
`Microcrystalline Cellu!OIC and
`Sodium CMC (Avicel ® RC591, FMC)
`Polysorbate 80
`Glycerin
`Flavorants
`F, D &: C Red #40
`Sodium Phosphate Dibasic
`Sodium Hydroxide
`Sodium Saccharin
`Water, Purified
`
`30.0 mg
`777.0 mg
`l.S ml
`8.16 g
`1.S mg
`187.S mg
`
`3.0 mg
`300.0 mg
`0.05 ml
`S.1 mg
`231.0 mg
`3.6 mg
`22.5 mg
`q.s.
`
`Ingredients
`
`Dextromethorpban HBr
`Propylene Glycol
`Ethanol (95%)
`Menthol, Natural
`Eucalyptus Oil
`Sucrose
`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
`
`EXAMPLE VII
`Liquid Cough Composition
`Amount/15 ml Dose
`30.0 mg
`1.74 g
`1.5 ml
`22.5 mg
`7.5 mg
`8.16 g
`7.5 mg
`187.5 mg
`
`3.0 mg
`0.05 ml
`5.1 mg
`231.0 mg
`30.0 mg
`300.0 mg
`3.6 mg
`q.s.
`
`Ingredients
`
`EXAMPLE VIII
`Liquid Cough Composition
`Amount/I 5 ml Dose
`
`Dextromethorphan HBr
`Sucrose
`Glycerin
`Sorbitol
`F, D k C Red #40
`Sodium Phosphate Dibasic
`Sodium Hydroxide
`Sodium Saccharin
`Propylene Glycol
`Ethanol (95%)
`Menthol
`Eucalyptus Oil
`Flavorants
`Water, Purified
`
`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.
`
`Ingredients
`
`EXAMPLE IX
`Liquid Cough Composition
`Amount/15 ml Dose
`30.0 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
`100.0 mg
`l.S ml
`22.5 mg
`7.5 mg
`0.05 ml
`q.s.
`
`Dextromethorphan HBr
`Sucrose
`Glycerin
`Sorbitol
`F, D k C Red #40
`Sodium Phosphate Dibasic
`Sodium Hydroxide
`Sodium Saccharin
`Propylene Glycol
`Phenol
`Ethanol (95%)
`Menthol
`Eucalyptus Oil
`Flavorants
`Water, Purified
`
`EXAMPLEX
`Compressed Tablet Composition
`
`Ingredients
`Dextromethorpban Base
`Benzocaine
`S Talc
`Flavorants
`Caramel MC #40
`Trisodium Phosphate Dodecabydrate
`Magnesium Stearate
`Saccharin
`IO Emdex
`
`Amount/2.25 g Lozenge
`
`5.0 mg
`1.25 mg
`90.0 mg
`15.8 mg
`69.4 mg
`40.0 mg
`45.0 mg
`15.0 mg
`q.s.
`
`Ingredients
`15 Dextrometborpban Base
`Propylene Glycol
`Ethanol (95%)
`Polyethylene Glycol (Carbowax 400)
`Sodium Saccharin
`Flavorants
`F, D &: C Red #40
`20 Phenol
`Purified Water
`
`EXAMPLE XI
`Liquid Spray Cough Composition
`Amount/3.5 ml Dose
`25.0 mg
`0.7 ml
`I.OS ml
`0.7 ml
`5.25 mg
`0.012 ml
`1.19 mg
`75.0 mg
`q.s.
`
`Ingredients
`25 Dextromethorphan Base
`Propylene Glycol
`Ethanol (95%)
`Polyethylene Glycol (Carbowax 400)
`Monobasic Sodium Phosphate
`Sodium Sacbarin
`30 Flavorants
`F, D &: C Red #40
`Purified Water
`
`EXAMPLE XII
`Liquid Spray Cough Composition
`Amount/3.5 ml Dose
`10.0 mg
`0.7 ml
`0.7 ml
`0.7 ml
`8.4 mg
`7.0 mg
`0.14 ml
`1.19 mg
`q.s.
`
`50
`
`The liquid of Example XII is made by adding the
`35 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
`40 added as a water solution with stirring. Purified water is
`added to volume with stirring.
`While particular embodiments of the subject inven(cid:173)
`tion have been described it will be obvious to those
`skilled in the art that various changes and modifications
`45 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:
`1. An antitussive composition, in dosage unit form,
`for peroral administration consisting essentially of a safe
`and effective amount of dextromethorphan and an oral(cid:173)
`ly-acceptable pharmaceutical carrier in the form of an
`aqueous-based liquid, or solid dissolvable in the mouth,
`55 selected from the group consisting of syrup, elixer,
`suspension, spray, lozenge, chewable lozenge, powder,
`and chewable tablet, the composition, or 10% artificial
`saliva solution thereof for solid dosage forms, being at a
`pH of about 8 to about 11, the carrier comprising a
`60 buffer system whereby the composition when mixed
`with saliva in the mouth is within such pH range.
`2. The composition of claim 1 wherein the composi(cid:173)
`tion has a basic buffer strength of at least about 0.01
`mEq base per dose, and from about 1 mg to abo