Note: Descriptions are shown in the official language in which they were submitted.
'''O 92/07559 PCI/US91/07773
- 2129676
--1--
DEXTROMETHORPHAN ANTITUSSIVE COMPOSITIONS
TECHNICAL FIELD
This invention is concerned with novel antitussive composi-
tions 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-
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
antitussive agent in commercial products as disclosed in the
PhYsician's Desk Reference for NonDrescriDtion Druqs, 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,
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
W o 92/o75~9 PCT/USsl/0777
2129676 - - 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 Pharmaceu-
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 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 Medi-
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 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-
ticals, 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,
,, 21~967 6
- 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. The commercial
products listed above are all described by their trade marks and 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 PharmacoloqY, 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 Triqqs. 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.
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.
WO 92/07559 . PCI /US91/077 7
,96~ 6 - 4 -
It is also an object of the subject invention to provide
methods for achieving rapid antitussive action from dextro-
methorphan compositions.
The subject invention involves pharmaceutical compositions
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
8 to about 11.
The subject invention also involves pharmaceutical composi-
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-accept-
able pharmaceutical carrier, the composition having a pH of from
about 8 to about 11.
The subject invention also involves pharmaceutical composi-
tions 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
amountn, 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"
-
~'0 92/07559 212 9 6 7 6 P ~ /US91/07773
- 5 -
means racemethorphan, 3-methoxy-17-methylmorphinan (dl-cis-
1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4a-imino-
ethanophenanthrene:
CH30
'~
~ ~ NCH3
Ij ~
and pharmaceutically-acceptable salts thereof. Preferred salts
of dextromethorphan include the hydrobromide salt.
The compositions of the subject invention preferably com-
prise 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 pharma-
ceutical 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
WO 92/07559 PCI'/US91/0777~
~,~29616 - 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 dextro-
methorphan, 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 subiect invention prefera-
bly 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 pharma-
ceutically-acceptable carrier preferably comprising a pharmaceu-
tically-acceptable buffer system. Examples of pharmaceutically-
acceptable 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 inven-
tion are phosphate buffer systems.
A preferred component of the carrier of the compositions ofthe 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
~ 2 ~ ~9 6 7 ~
- 7 -
preferably have a ratio of microcrystalline cellulose to
carboxymethylcellulose sodium of from about 20:1 to abcut 1:1;
more preferably from about 15:1 to about ~:1, more preferably
still from about 10:1 to about 5:1.
A preferred mixture of microcrystalline cellulose and
carboxymethylcellulose sodium is Avicel0 RC591, a commercially
available microcrystalline cellulose marketed by FMC Corporation,
Food and Pharmaceutical Products Division, Philadelphia, Pennsyl-
vania. Avicel~ RCS91 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
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 "Avicel0 RC-CL Microcrystalline Cellulose".
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 O.S% 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
~ ~ ~~ ~7
- 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. Homoto, "Artificial Saliva", Journal of Dental
Research, Vol. 42 (1963), pp. 1183-1197.
Dextromethorphan is relatively insoluble in water at the pH
of the compositions of the subject invention. ~herefore, 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 pre-
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
20 mentho1, anethol, camphor, thymol, methyl salicylate, eucalyptus
oil and peppermint oil; other flavoring agents; thickening
agents, such as carboxymethylcellulose, sodium carboxymethyl-
cellulose, cellulose, glycerine and polyethylene glycol; coloring
agents; preservatives, such as sodium benzoate and cetylpyri-
25 dinium chloride; miscellaneous ingredients, such as potassiumsorbate, 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 ingredi-
ents 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
T~
"1O 92/07559 21 29 6 7 6 PCT/VS91/07773
g
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 composi-
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
W o 92/075~9 pc~r/ussl/o777?
- 10 -
~96~ 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 (prefer-
ably 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), 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 (prefer-
ably 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 admini-
"'O 92/07559 212 9 6 7 6 PCl'/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 dextro-
methorphan 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
Liauid Couqh ComDosition
Inqredients Amount/15 ml Dose
Dextromethorphan HBr 30.0 mg
Z0 Propylene Glycol 1.74 9
Ethanol (95%) 1.5 ml
Menthol, Natural 12.5 mg
Eucalyptus Oil 7.55 mg
Flavorants 0.05 ml
Sucrose 7.65 9
Carboxymethylcellulose (CMC) 7.5 mg
Microcrystalline Cellulose and
Sodium CMC (Avicel~ RC591, FMC)187.5 mg
Polysorbate 80 3.0 mg
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
3~ Water, Purified q.s.
WO 92/07559 PCI/US91/0777~
- 12 -
~96~ 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
Liquid Couqh ComDosition
Inqredients Amount/15 ml Dose
Dextromethorphan HBr 15.0 mg
Propylene Glycol 777.0 mg
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
Sodium Saccharin 22.5 mg
Water, Purified q.s.
EXAMPLE III
Liquid Couqh ComDosition
Ingredients Amount/15 ml Dose
Dextromethorphan HBr 30.0 mg
Propylene Glycol 1.74 9
Ethanol (95%) 1.5 ml
Menthol, Natural 22.5 mg
Eucalyptus Oil 7.5 mg
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 9
Glycerine 750.0 mg
2129676
~vo 92/07559 P ~ /US91/07773
- - 13 -
Sodium Hydroxide 3.0 mg
Water, Purified q.s.EXAMPLE IV
Liauid Couqh Composition
Inqredients Amount/15 ml Dose
Dextromethorphan HBr 30.0 mg
Sucrose 8.16 9
Carboxymethylcellulose (CMC) 7.5 mg
Microcrystalline Cellulose and187.5 mg
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
Sodium Phosphate Dibasic 231.0 mg
Sodium Hydroxide 3.6 mg
Sodium Saccharin 30.0 mg
Propylene Glycol 1.74 9
Ethanol (95X) 1.5 ml
Menthol 22.5 mg
Eucalyptus Oil 7.5 mg
Flavorants 0.05 ml
Water, Purified q.s.
EXAMPLE V
Liauid Couqh ComDosition
Ingredients Amount/15 ml Dose
Dextromethorphan HBr 20.0 mg
Sucrose 8.16 9
CMC 7.5 mg
Microcrystalline Cellulose and187.5 mg
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
Sodium Phosphate Dibasic 231.0 mg
-
W o 92/07559 P ~ /US91/07773
- 14 -
Sodium Hydroxide 5.0 mg
~9 61 6 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 ComDosition
Inqredients Amount/15 ml Dose
Dextromethorphan HBr 30.0 mg
Propylene Glycol 777.0 mg
Ethanol (95%) 1.5 ml
Sucrose 8.16 9
CMC 7.5 mg
Microcrystalline Cellulose and187.5 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.
~XAMPLE VII
Liquid Cough ComDosition
Inqredients Amount/15 ml Dose
Dextromethorphan HBr 30.0 mg
Propylene Glycol 1.74 9
Ethanol (95%) 1.5 ml
Menthol, Natural 22.5 mg
Eucalyptus Oil 7.5 mg
Sucrose 8.16 9
wo 92/07~S9 2 I 2 9 6 7 6 PCI'/US91/07773
- 15 -
CMC 7.5 mg
Microcrystalline Cellulose and 187.5 mg
Sodium CMC (Avicel~ RC591, FMC)
Polysorbate 80 3.0 mg
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
Sodium Hydroxide 3.6 mg
Water, Purified q.s.
EXAMPLE VIII
Liauid Couqh ComDosition
Inqredients Amount/15 ml Dose
Dextromethorphan HBr 25.0 mg
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
Ethanol (95%) 1.5 ml
Menthol 22.5 mg
Eucalyptus Oil 7.5 mg
Flavorants 0.05 ml
Water, Purified q.s.
EXAMPLE IX
Liauid Couqh ComDosition
Inqredients Amount/15 ml Dose
Dextromethorphan HBr 30.0 mg
Sucrose 8.16 9
Glycerin 300.0 mg
-
WO 92/07559 PCl'/US91/0777?
- 16 -
2 ~ 2 9 6 ~ 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
ComDressed Tablet ComDosition
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 SDraY Couqh ComDosition
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.
~vo 92/075~9 21 2 9 6 7 6 PCl /US91/07773
- 17 -
EXAMPLE XII
Liauid SDraY Couqh Comoosition
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 Phosphate8.4 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:
