Note: Descriptions are shown in the official language in which they were submitted.
WO 94/08551 ~ ~ ~ 6 ~ , ~ PCT/US93/08887
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PHARMACEUTICAL COMPOSITIONS AND METHODS
FOR TREATING COLD SYMPTOMS
BACKGROUND OF THE INVENTION
The present invention relates to orally or nasally administrable
pharmaceutical compositions comprising at least one pharmaceutical
active, 3-1-menthoxy propane 1,2-diol (herein referred to as "MPD")
and pharmaceutically-acceptable carrier material(s). The present
invention also relates to methods for treating cough, cold, cold-like,
allergy and/or flu symptoms in a human or lower animal by adminis-
tering, orally or nasally, a composition comprising MPD.
Pharmaceutical compositions safe and effective for treating
colds, flu, and allergies are well known. Over-the-counter medica
tions provide symptomatic relief of such illnesses. Typical symptoms
of the common cold are mild malaise, sore throat and nasal complaints.
Nasal discharge, nasal congestion and/or sneezing frequently are
present. Also common are sore, dry or scratchy throat and hoarseness
and cough. Other symptoms may include mild burning of the eyes, loss
of smell and taste, a feeling of pressure or fullness in the sinuses
or ears, headache, and vocal impairment. Flu symptoms are similar but
usually of greater severity, including fever, generalized aches and
pains, fatigue and weakness, and chest discomfort. Allergy symptoms
are more akin to the common cold, with more frequent/severe sinus
pressure, drainage and headaches.
- Prior art formulations for treating cough, cold, cold-like,
allergy and/or flu symptoms and the discomfort, pain, fever and
general malaise associated therewith typically contain one or more of
the pharmaceutical actives which are analgesics, anesthetics, antihis-
tamines, decongestants, cough suppressants, antitussives and expector-
ants.
It is an object of the present invention to provide compositions
and methods useful for treating cough, cold, cold-like, allergy and
flu symptoms in humans and lower animals in need of such treatment.
Another object is to provide such compositions and methods having
increased perceived efficacy, e.g., speed of relief and/or duration of
relief, and/or improved aesthetics.
These and other objects of the present invention will become
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readily apparent from the detailed description which follows.
All percentages and ratios used herein are by weight, and all
measurements are made at 25'C, unless otherwise specified.
SUMMARY OF THE INVENTION
The present invention is directed to pharmaceutical compositions
comprising: (a) a safe and effective amount of at least one pharma-
ceutical cold active; (b) 3-1-menthoxy propane 1,2-diol; and (c) a
pharmaceutically-acceptable carrier material suitable for oral or
nasal administration.
The present invention is also directed to methods for treating
cough, cold, cold-like, allergy, and flu symptoms in a human or lower
animal, said method comprising administering to a human or lower
animal in need of such treatment, by oral or nasal administration, a
composition comprising 3-1-menthoxy propane 1,2-diol.
~FTAILED DESCRIPTION OF THE INVENTION
The present invention relates to pharmaceutical compositions
comprising: (a) at least one pharmaceutical cold active; (b) 3-1-
menthoxy propane 1,2-diol ("MPD"); and (c) pharmaceutically-acceptable
carrier material suitable for oral or nasal administration. The
components of the compositions according to the present invention, and
representative amounts, as well as the present invention methods are
described in detail as follows.
Pharmaceutical Cold Actives:
The pharmaceutical compositions according to the present inven
tion comprise pharmaceutical cold actives useful for treating cough,
cold, cold-like, allergy and/or flu symptoms. Such pharmaceutical
actives are well known, and are generally recognized as being an
active having analgesic, anti-inflammatory, anesthetic, antihistamine,
decongestant, cough suppressant, demulcents, antitussive, and/or
expectorant properties.
The compositions of this invention therefore contain one or more
known pharmaceutical cold actives, particularly those commonly
utilized in cough/cold preparations, such as, for example, a decon-
gestant such as pseudoephedrine, phenylpropanolamine, phenylephrine
and ephedrine, their pharmaceutically acceptable salts; an antitussive
such as dextromethorphan, chlophedianol, carbetapentane, caramiphen,
noscapine, diphenhydramine, codeine, menthol, hydrocodone, hydromor-
phone, fominoben, their pharmaceutically-acceptable salts; an expec-
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torant or mucolytic such as glyceryl guaiacolate, terpin hydrate, ammonium
chloride, N-acetylcysteine and bromhexine, ambroxol, their pharmaceutically-
acceptable salts; and an antihistamine such as chlorpheniramine,
brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine,
azatadine, doxylamine, tripelennamine, cyproheptadine, hydroxyzine,
clemastine, carbinoxamine, phenindamine> bromodiphenhydramine, pyrilamine,
their pharmaceutically-acceptable salts, as well as the non-sedating
antihistamines which include acrivastine, AHR-11325, astemizole, azelastine,
cetirizine, ebastine, ketotifen, lodoxamide> loratidine, levocabastine,
mequitezine> oxatomide, setastine, tazifylline, temelastine, and
terfenadine, their pharmaceutically-acceptable salts: all of these
components, as well as their acceptable dosage ranges are described in the
following: U.S. Patent 4,783,465 to Sunshine et al., issued November 8,
1988, U.S. Patent 4,619,934 to Sunshine et al.> issued October 28, 1986.
Also useful are bronchodilators such as terbutaline, atropine,
aminophylline, epinephrine, isoprenaline, metaproterenol, bitoterol,
theophylline and albuterol. Also used are analgesic compounds such as
acetylsalicylic acid, acetaminophen, ibuprofen, and naproxen; and topical
anesthetics/analgesics such as phenol, benzocaine, hexyl resorcinol, and
dyclonine.
The compositions of the present invention comprise a safe and
effective amount of at least one pharmaceutical cold active. The phrase
"safe and effective amount", as used herein, means an amount of a compound
or composition high enough when administered orally or nasally to
significantly positively modify 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. The safe and effective amount of the
pharmaceutical cold 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, the specific pharmaceutical cold active employed, the
particular pharmaceutically-acceptable carrier utilized, and like factors
within the knowledge and expertise of the attending physician. Typically,
the pharmaceutical cold actives) comprise from about 0.001 to about 99.9,
by weight, of the pharmaceutical compositions of the present invention,
preferably from about O.OOli to about 75i> and most preferably from about
0.01 to about 30%.
i. ;
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3-1-Menthoxy Propane 1 2-Diol:
The pharmaceutical compositions of the present invention also
comprise 3-1-menthoxy propane 1,2-diol ("MPD"). This material is described
in detail in U.S. Patent 4,459.425, issued July 10, 1984 to Amano et. al.
Whi 1 a not to be 1 i mi ted by theory, i t i s bel i eyed that the benefi is
obtai ned
by the use of MPD i n the composi ti ons of the present i nventi on are the
resul t of the uni que cool i ng profi 1 a for thi s compound . MPD i s
commerci al 1 y
available, being sold by Takasago Perfumery Co., Ltd., Tokyo, Japan.
MPD typically comprises from about 0.001% to about 10% by weight of
the pharmaceutical compositions of the present invention, preferably from
about 0.01% to about 5%, and most preferably from about 0.01% to about 0.5%.
Pharmaceutically-Acc~~table Carrier Material'
The term "pharmaceutically-acceptable carrier materials", as used
herein, means one or more compatible solid or liquid filler diluents or
encapsulating substances which are suitable for oral and/or nasal
administration to a human or lower animal. The term "compatible", as used
herein, means that the components of the compositions of the present
invention are capable of being commingled with the pharmaceutical cold
active, and with each other, in a manner such that there is no interaction
which would substantially reduce the pharmaceutical efficacy of the
compositions under ordinary use situations. Pharmaceutically-acceptable
carrier materials must, of course, be of sufficiently high purity and
sufficiently low toxicity to render them suitable for administration to the
human being treated.
The choice of pharmaceutically-acceptable carrier materials to be
used in conjunction with the pharmaceutical cold active of the present
compositions is basically determined by the dose form for the compositions.
The preferred dosage forms are liquid solutions, liquid suspensions,
tablets, capsules and the like, comprising a safe and effective amount of
the pharmaceutical actives. Pharmaceutically-acceptable carrier materials
suitable for the preparation of dosage forms for oral and nasal (e. g., nasal
sprays) administration are well-known in the art. Their selection will
depend on secondary considerations like taste, cost, shelf stability, which
are not critical for the purposes of the present invention, and can be made
without difficulty by a person skilled in the art. Preferably the present
invention compositions comprise from about 0.1% to about 99.99% of one or
more pharmaceutically-acceptable carrier materials.
t,.,
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Various oral dosage forms can be used, including such solid forms as
tablets, capsules, granules, lozenges and bulk powders and liquid forms such
as syrups and suspensions. These oral forms comprise a safe and effective
amount of the pharmaceutical cold active component. Solid oral dosage forms
preferably contain from about 0.1% to about 99%, more preferably from about
25% to about 99%, and most preferably from about 50% to about 99% of the
pharmaceutical cold active component. Liquid oral dosage forms preferably
contain from about 0.001% to about 25% and more preferably from about 0.001%
to about 10% and most preferably from about 0.01% to about 5% of the
pharmaceutical cold active component.
Tablets can be compressed, molded, triturated, enteric-coated, sugar
coated, film-coated or multiple compressed, containing suitable binders.
lubricants, diluents, disintegrating agents, coloring agents, flavoring
agents, preservatives and flow-inducing agents. Also useful are soft
gelatin capsules.
Techniques and compositions for making solid oral dosage forms are
described in Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics.
Vol. 7. (Banker and Rhodes, editors), 359-427 (1979). Techniques and
compositions for making tablets (compressed and molded), capsules (hard and
soft gelatin) and pills are described in Remington's Pharmaceutical Sciences
(Arthur Osol, editor). 1553-1593 (1980).
Liquid oral dosage forms include aqueous and nonaqueous solutions,
emulsions, pseudo emulsions, suspensions, and solutions and/or suspensions
reconstituted from non-effervescent granules, containing suitable solvents,
preservatives, emulsifying agents, suspending agents, diluents, sweeteners.
coloring agents, and flavoring agents. Specific examples of
pharmaceutically-acceptable carriers and excipients that may be used to
formulate oral dosage forms, are described in U.S. Patent 3,903.297, Robert,
issued September 2, 1975. Although water itself may make up the entire
carrier, typical liquid formulations preferably contain a co-solvent, for
example, propylene glycol, polyethylene glycol,
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WO 94/08551 1 ~ s s ~ 7 » PCT/US93/0888' 4~
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alcohol, glycerin, sorbitol solution and the like, to assist solubili-
zation and incorporation of water-insoluble ingredients, such as
flavoring oils and the like into the composition.
Other optional ingredients well known to the pharmacist's art may
also be included in amounts generally known for these ingredients, for
example, natural or artificial sweeteners, flavoring agents, colorants
and the 1 i ke to provide a pal atabl a and pl easant 1 ooki ng fi nal prod
uct, antioxidants, for example, butylated hydroxy anisole or butylated
hydroxy toluene, and preservatives, for example, methyl or propyl
paraben, potassium sorbate, or sodium benzoate, to prolong and enhance
shelf life. A preferred optional component is also materials other
than MPD having cooling properties, such as menthol and menthol-like
compounds such as N-ethyl-p-menthane-3-carboxamide (preferably at from
about 0.001% to about 5f., more preferably from about 0.001% to about
0.5%), and mixtures thereof. A preferred optional component is also
caffeine.
Method of Treatment:
The present invention also relates to a method for treating
cough, cold, cold-like, allergy and flu symptoms in a human or lower
animal. Said method comprises administering to a human or lower
animal in need of such treatment, by oral or nasal administration, a
composition comprising MPD. Preferred pharmaceutical compositions for
administration according to the present invention method comprise from
about 0.001% to about 10% (preferably from about 0.01% to about 0.5Ye)
of MPD, and from about 0.1% to about 99.999% (preferably from about
709:-.to about 99.99%) of~harmaceutically-acceptable carrier
material(s). Preferred is administering, either orally or nasally, a
safe and effective amount of a composition according to the present
invention. Most preferred is oral administration.
The following examples further describe and demonstrate embodi-
ments within the scope of the present invention. These examples are
given solely for the purpose of illustration and are not to be con-
strued as a limitation of the present invention as many variations
thereof are possible without departing from the spirit and scope.
Example 1 - Couah Svrup
Ingredient Amount/15m1 dose
Dextromethorphan HBr 20 mg
Glyceryl Guaiacolate 200 mg
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Sucrose 8.16 grams
Alcohol 1 ml
.Citric Acid, Anydrous 4 mg
Sodium Citrate 300 mg
MPD1) 15 mg
WS-32) 0.75 mg
Menthol 7.5 mg
Coloring Agent 4.5 mg
Water, Purified Q.S. to 15 ml
1) 3-1-menthoxy propane 1, 2-diol, supplied by Takasago
Perfumery Co., Ltd., Tokyo, Japan
2) N-ethyl-p-menthane-3-carboxamide, supplied by Sterling
Drugs
This composition is prepared.by first dissolving the dextromethor-
phan and glyceryl guaiacolate in alcohol and then adding with constanx
mixing the menthol, MPD and WS-3. In separate containers dissolve the
sucrose in a small portion of the water, dissolve the coloring agent
i n a separate smal 1 part i on of the water, and i n st i 11 another con-
tainer dissolve the sodium citrate and citric acid in a small portion
of the water. Finally, all the premixes and the remaining water are
mixed with constant mixing to prepare a composition of the present
invention having 20 mg of dextromethorphan and 200 mg of glyceryl
guaiacolate per 15 ml of composition.
Administration (by drinking 15 ml) of this composition to a human
patient having a cough associated with the common cold provides rapid,
long-lasting relief of t-he cough in said human patient.
Example 2 - Couqh Droe
% Composition
Ingredient (y W/WJi
Menthol, Natural 0.2211
Eucalyptus Oil 0.1455
MPD 0.0700
WS-3 0.0300
FD&C Blue ~1 0.0022
Sugar QS*
Low DE Corn Syrup QS*
*60/40 Sugar/Low DE Corn Syrup (before cook); candy base
used.
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WO 94/08551 PCT/US93/0888'
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This composition is prepared by standard drop forming techniques.
Administration (by sucking) of drops to a human patient having a
cough associated with the common cold provides rapid, long lasting
relief of the cough in said human patient.
10
20
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