Note: Descriptions are shown in the official language in which they were submitted.
3qli
Zi:P17923
HEATED ORAL ANTlTU$SIVE COMPOS;TIONS
Gordon F. Brunner
David A. Nichols
TECHNICAL FIELD
The present invention relates to heated antitussive oral pharma-
ceutical compositions containing a volatile essential oil component
which has a vapor pressure of from about 0.05mm to about 15.0mm at
60C.
BACKGROUND OF THE INVENTION
The cough reflex is an important mechanism whereby secretions
from the lungs and airways are removed. Generally, such secretions
are removed by the mucociliary escalator. However, when this mecha-
nism is defective, or becomes overwhelmed by, for example, excessive
secretions, cough then becomes a principal means of secretion removal.
The cough reflex is initiated by stimulation of mechanical and
irritant receptors and is controlled by afferent pathways within the
vagus tX), glossopharyngeal (IX), and superior laryngeal nerves to the
cough center in the brainstem. Cough can be caused by, for example,
foreign bodies, dust, mucus, debris, gases and smoke in the lower
respiratory tract. Irritation of various sensory nerves in the nose,
sinuses, pharynx, ears, stomach, pericardium or diaphragm can also
produce coughing. In many of these conditions, chronic or paroxysmal
cough, however, can be exhausting and debilitating, particularly when
it interferes with sleep.
Oral cough preparations, such as tablets, lozenges, syrups,
solutions, suspensions and the like, containing an effective anti-
tussive agent have long been used for the symptomatic relief of
coughs. The most popular of such preparations contain either dextro-
methorphan (or its hydrobromide salt) or codeine (or its sulfate salt)
as the active antitussive agent. These remedies, among many others,
are fully described in Drua Evaluations, 6th Ed., Chapter 21 (The
American Medical Association, 1986).
Mixtures of honey and lemon juice have been disclosed as useful
in treating cough. It has also been disclosed that hot water may also
provide some relief from cough. Aromatics have also been used as a
flavoring agent in cold and flu remedies. Many of these treatments
are described in Medical Surqical Nursinq, 6th Ed. (The C.V. Mosby
Company, 1975), pp. 553-555. However, while such remedies may soothe
z 2i~17923
or warm the throat, they do not provlde any significant antitussive or
decongestant actlon.
It has now been discovered that oral antitussive pharmaceutical
compositions having a temperature of from about 35'C to about 70~C and
which contain a volatile essential oil component having a vapor pres-
sure of from about 0.05mm to about 15.0mm at 60'C along Wi.n a pharma-
ceutically acceptable oral carrier having a viscosity of from about
150 cps to about 800 cps (at 25-C) provide improved antitussive and
decongestant efficacy and/or improved relief as seen by the product
user.
It is therefore an object of the present inventian to provide
heated oral pharmaceutical compositions containing certain volatile
essential oils which are highly efficacious in the treatment of cough.
It is still a further object of the present invention to provide
a method of using these same pharmaceutical compositions in the treat-
ment of cough in humans or animals.
SUMMARY OF THE INVENTION
The present invention relates to an oral pharmaceutical composi-
tion for the treatment of cough comprising: (a) from about 0.01% to
about 0.25% of a volatile essential oil component having a vapor
pressure of from about 0.05mm to about l5.0mm at 60-C; and (b) from
about 50% to about 99r. of a pharmaceutically acceptable oral carrier
having a viscosity of from about 150 cps to about 800 cps, wherein
said pharmaceutical composition has a temperature of from about 35-C
to about 70-C.
Preferably the volatile essential oil component is selected from
the group consisting of menthol, eucalyptus oil, eugenol, camphor,
thymol, anethole, eucalyptol, cineole, peppermint oil, cuminal, and
citral and mixtures thereof.
Also provided are methods for the treatment of cough in humans or
; ; animals which comprise orally administering to said human or animal a
safe and effective amount of these heated pharmaceutical compositions.
All percentages and ratios used herein are by weight unless
otherwise indicated. All vapor pressures used herein are in milli-
meters of mercury and all viscosities are in centipoises at 25-C.
DETAILED DESCRIPTION Of THE DEVELOPMENT
More specifically, the present invention provides oral antitus-
sive pharmaceutical compositions and methods for the treatment of
cough in humans or animals afflicted with the same. The compositions
-3 2'J179Z3
of the present invention comprise: (a) from about 0.01% to about
0.2SY., preferably from about 0.02% to about 0.2% and most preferably
from about 0.05% to about 0.15% of a volatlle essential oll component
having a vapor pressure of from about O.OSmm to about 15.amm, prefera-
S bly from about n.5mm to about 7.0mm and most preferably from aboutO.Smm to about 2.0mm at 60'C; and (b) from about 50% to about 99%,
preferably from about 70% to about 99% of a pharmaceutically accept-
able oral carrier having a viscosity of from about 150 cps to about
800 cps, preferably from about 150 cps to about 700 cps and most
preferably from about lSO cps to about 600 cps and wherein said
pharmaceutical composition has a temperature of from about 35'C to
about 70 C, preferably from about 40 C to about 70 C, more preferably
from about 50-C to about 65-C and most preferably from about 55-C to
about 60-C.
Preferably, the volatile essential oil component is selected from
the group consisting of menthol, eucalyptus oil, eugenol, camphor,
thymol, anethole, eucalyptol, cineole, peppermint oil, cuminal, and
citral and mixtures thereof.
By safe and effective amount is meant that amount which provides
antitussive efficacy thereby alleviating or preventing cough at a
reasonable benefit/risk ratio, as is attendant with any medical
treatment. Obviously, the amount of the antitussive pharmaceutical
composition which is administered will vary with such factors as the
particular condition that is being treated, the severity of the
condition that is being treated, the duration of the treatment, the
physical condition of the patient, the nature of concurrent therapy
(if any), the specific formulation and carrier employed, and the
solubility and concentration of the antitussive used.
VOLATILE ESSENTIAL OI~S
The volatile essential oil components useful in the present
invention have a vapor pressure at 60-C of from about O.OSmm to about
15.0mm.
Volatile essential oils are found in various plant organs and
- tissues. They usually consist of the savory and odorous principles of
the plants in which they exist. Additionally, they either pre-exist
in the tissues or are produced by the reaction of certain constituents
when the tissues are brought into contact with water. Volatile
aromatics are also sometimes formed through destructive distillation,
~4~ 2~117923
as the oils of tar and amber These aromatics are sometimes referred
to as pvrolea..
Certain volatile oils separate into a solid and liquid portion
upon standing. The solid portion is generally referred to as stearop-
S tene (e.g. thymol, camphor, and menthol), and the liquid portion iscalled eleoDtene. The useful volatile essential oil component is
purified from these.
Volatile essential oil components which are useful in the compo-
sitions of the present invention include organic acids, such as
acetic, benzoic, cinnamic, phenylacetic, etc.; a7coho1s like benzyl
alcohol, borneol, cinnamyl alcohol, citronellol, geraniol, linalool,
menthol, phenylethyl alcohol, terpineol, etc.; a7dehydes such as
anisaldehyde, cinnamaldehyde, benzaldehyde, citral, piperonal or
heliotropin, salicylaldehyde, vanillin, etc,; ketones like carvone,
camphor, thujone, pulegone, etc.; esters such as bornyl acetate,
methyl salicylate, benzyl benzoate, geranyl acetate, linalyl acetate,
etc.; pheno7s such as thymol, carvacrol, chavicol, etc.; pheno7 ethers
like anethole, eugenol, safrol, etc.; others such as eucalyptus oil,
eucalyptol, cuminal and peppermint oil and many other more complex
compounds, such as coumarin, indole, etc. Many of these products are
found in flower oils and are used in the production of synthetic
perfumes. Mixtures of these volatile essential oils may also be used.
Preferably the volatile essential oil component is selected from
the group consisting of menthol, eucalyptus oil, eugenol, camphor,
thymol, anethole, eucalyptol, cineole, peppermint oil, cuminal, and
citral and mixtures thereof.
It has been found that the compositions of the present invention
containing these volatile essential oil components with these specific
vapor pressures provide improved antitussive and decongestant efficacy
and/or improved relief as seen by the product user.
The usual approximate vapor pressures (at 60C) for preferred
volatile aromatic or essential oils are indicated in the following
table:
zi~7923
APPROXIMATE VAPOR
COMPONENT PRESSURE (mm of Hq)
Menthol 1 0
Eucalyptus Oil 10.0
Eugenol <1.0
Camphor >1.5
Thymol 1.0
Anethole 1 0
Eucalyptol 12.0
Peppermint 1.0
Cuminal 1.0
Citral 1.0
OPTIONAL COMPONENTS
Preferably the oral antitussive csmpositions of the present
invention contain other known th~rapeutic agents typically used in
cough/cold preparations described below. The compositions of the
present invention typically contain from about O.OlYo to about 1.0% of
such agents.
A particularly preferred optional therapeutic agent is an oral
antitussive drug. As used herein, the term "oral antitussive drug"
means a drug that is taken by mouth and acts systemically to relieve
cough (see Federal Register, Vol. 52, No. 155, 12 August 1987, page
30055)-
Useful recognized oral antitussive drugs include, but are not
limited to, for example, the non-narcotic types such as dextromethor-
phan and its acid salts, preferably the hydrobromide, chlophedianol
hydrochloride~ carbetapentane citrate, caramiphen edisylate, diphenhy-
dramine and its hydrochloride salt, fominoben, and the like, and the
narcotic type such as codeine and its sulfate or phosphate salts,
noscapine hydrochloride, hydrocodone and its bitartrate salt, hydro-
morphone hydrochloride, and the like. The usual adult dosages for
such antitussives, which may also be utilized per dose in the subject
compositions, are indicated in Table I.
~ABLE I 2~1~L7923
Usual Adult
Oral Antitu$stve Orug Oose ~mq)
Dextromethorphan HBr 10-30
Chlophedianol HCl 15-25
Carbetapentane citrate 15-30
Caramiphen edisylate 15-20
Noscapine HCl 15-30
Diphenhydramine HCl 15-25
Codeine sulfate 10-20
Hydrocodone bitartrate S-10
Hydromorphone HCl 2
Fominoben 80-160
Preferred oral antitussive agents are dextromethorphan, codeine
lS and diphenhydramine and pharmaceutically acceptable salts thereof and
mixtures thereof. Even more preferred are dextromethorphan and
codeine, pharmaceutically acceptable salts thereof and mixtures
thereof. Most preferred is dextromethorphan and its pharmaceutically
acceptable salts.
As used herein, the term "oral decongestant drug" means a drug
that is taken by mouth and acts systemically to relieve congestion
(see Federal Register, Vol. SO, No. 10, lS January 1985, pp. 2220-
2240). Preferred oral decongestant drugs include pseudoephedrine
hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydro-
chloride and ephedrine hydrochloride and mixtures thereof.
The volatile essential oil components are used along with a
suitable liquid oral carrier. Liquid oral carriers useful in the
present invention have a viscosity ranging from about lSO cps to about
800 cps, preferably from about lSO cps to about 700 cps and most
preferably from about 150 to about 600. Various liquid oral dosage
forms can be used, including syrups, suspensions and solutions.
These oral forms comprise a safe and effective amount, usually at
least about 0.01% of the active component. Liquid oral dosage forms
preferably contain from about O.OlY, to about 0.25%, more preferably
from about 0.02% to about 0.2% and most preferably from about 0.05% to
about 0.15% of the volatile essential oil component.
~7~ 2~17923
Liquid oral dosage forms lnclude aqueous and nonaqueous solu-
tions, emulsions, suspensions, solutions and/or suspensions recons-
tituted from non-effervescent granules, containing suitable solvents,
preservatives, emulsifying agents, suspending agents, diluents,
sweetening agents, coloring agents, and flavoring agents. Preferred
carriers for oral administration include water, simple syrup, poly-
ethylene glycol, alcohol, corn syrup, invert sugar, gelatin, propylene
glycol, ethyl oleate, cottonseed oil and sesame oil and mixtures
thereof. 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,
incorporated by reference herein.
Since many of the optional oral antitussive drugs are generally
used in the form of a water-soluble salt, they can be readily incor-
I5 porated into conventional aqueous-based cough syrups and solution
formulations. Water-insoluble or poorly soluble antitussives, gener-
ally in base form, may also be incorporated into aqueous-based orally
acceptable pharmaceutical carriers such as dispersions, suspensions,
oil-in-water emulsions and the like by means of suitable dispersing,
suspending or emulsifying agents, respectively, which are readily
apparent to those skilled in the art of pharmaceutical formulations.
In preparing the pharmaceutical compositions of the present
invention, the volatile essential oil components are incorporated into
an aqueous-based orally acceptable pharmaceutical carrier consistent
with conventional pharmaceutical practices. An "aqueous-based orally
acceptable pharmaceutical carrier" is one wherein the entire or
predominant solvent content is water. Typical carriers include simple
aqueous solutions, syrups, dispersions and suspensions, and aqueous
based emulsions such as the oil-in-water type. The most preferred
carrier is a solution or suspension of the pharmaceutical composition
in an aqueous vehicle containing a suitable suspending agent. Suit-
able suspending agents include Avicel RlC-591 (a microcrystalline
cellulose/sodium carboxymethyl cellulose mixture available from FMC),
guar gum and the like. Such suspending agents are well known to those
skilled in the art. While the amount of water in the compositions of
this invention can vary over quite a wide range depending upon the
total weight and volume of volatile essential oil component and other
optional active and non-active ingredients, the total water content,
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based on the weight of the final composition, will generally range
from about 20 to about 75%, and, preferably, from about 20 to about
40%, by weight/volume.
Although water itself may make up much of the entire carrier,
typical cough formulations preferably contain a co-solvent, for
example, propylene glycol, glycerin, sorbitol solution and the like,
to assist solubilization and incorporation of water-insoluble ingre-
dient, flavoring oils and the like into the composition. In general,
therefore, the compositions of this invention preferably contain from
about 5 to about 25 volume/volume percent and, most preferably, from
about 10 to about 20 volume/ volume percent, of the co-solvent.
If required, to provide and maintain the subject compositions at
a pH of from about 2 to about 10 and preferably from about 4 to about
7, buffers consistent with conventional pharmaceutical practices are
generally utilized such as, for example, sodium citrate buffer, sodium
phosphate buffer, and the like. The compositions of this invention
may optionally contain one or more other known therapeutic agents,
particularly those commonly utilized in cough/cold preparations, such
as, for example, an analgesic such as acetaminophen and ibuprofen; an
expectorant or mucolytic such as glyceryl guaiacolate, guaiacolate,
terpin hydrate, ammonium chloride, N-acetylcysteine and ambroxol; and
an antihistamine such as chlorpheniramine maleate, doxylamine suc-
cinate, brompheniramine maleate and diphenhydramine hydrochloride:
all of which are described in U.S. Patent 4,619,934 to Sunshine et
al., issued October 28, 1986, which is incorporated by reference
herein. Also useful are bronchodilators such as theophylline and
albuterol.
The subject compositions are then heated to a temperature of from
about 35-C to about 70-C, preferably from about 40-C to about 70-C,
more preferably from about 50-C to about 65-C and most preferably from
about 55-C to about 60-C. By ~heating" herein is meant radiant,
conductive, or convective exposure to energy of a type which imparts
thermal energy to the product being heated. Suitable methods of
heating include conventional, infrared, convection and microwave
heating. Most preferred is microwave heating.
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
-9- 2~.J179~3
and the like to provide a palatable and pleasant looking final pro-
duct; antioxidants, ~or e~ample, butylated hydroxy an~sole or butylat-
ed hydroxy toluene, and preservatives, for example, methyl or propyl
paraben or sodium benzoate, to prolong and enhance shelf life.
METHOO OF TREATMENT
The present invention also encompasses methods of treating cough
in humans or lower animals through administering, to the human or
lower animal in need of such treatment, a safe and effective amount of
a pharmaceutical composition comprising: (a) from about 0.01% to
about 0.25%, preferably from about 0.02% to about 0.2% and most
preferably from about 0.05% to about O.l5YO of a volatile essential oil
component having a vapor pressure of from about 0.05mm tD about
15.0mm, preferably from about O.5mm to about 7.0mm and most preferably
from about O.OSmm to about 2.0mm at 60-C; and (b) from about 50% to
about 99%, preferably from about 70% to about 99% of a pharmaceuti-
cally acceptable oral carrier having a viscosity of from about 150 cps
to about 800 cps, preferably from about 150 cps to about 700 cps and
most preferably from about 150 cps to about 600 cps, wherein said
pharmaceutical composition has a temperature of from about 35~C to
about 70C, preferably from about ~0C to about 70-C, more preferably
from about 50-C to about 65-C and most preferably from about 55C to
about 60-C.
The amount of the pharmaceutical composition administered depends
upon the percent of active ingredients within its formula, which is a
function of the amount of the volatile essential oil components
required per dose, stability, release characteristics and other
pharmaceutical parameters. Usually from about 150 mg/kg to about 3600
mg/kg per day, preferably from about 150 mg/kg to about 2000 mg/kg per
day and most preferably from about 150 mg/kg per day to about 1000
mg/kg per day of the pharmaceutical composition is administered as
described herein. This amount can be given in a single dose or,
preferably, in multiple (two to six) doses repeatedly over the course
of treatment. Generally, each individual dosage of the pharmaceutical
compositions of the present invention range from about 100 mg/kg to
about 600 mg/kg, preferably from about 75 mg/kg to about 300 mg/kg and
most preferably from about 50 mg/kg to about 150 mg/kg. While dosages
higher than the foregoing are effective to prevent cough, care must be
taken, as with any drug, in some individuals to prevent adverse side
effects.
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The compositions and methods described herein are used in an art
recognized manner to provide antitUss~ve act~vity.
The following non-limlting e~amples illustrate embodiments of the
subject invention wherein both essential and optional ingredients are
combined. It is to be understood that these examples are for illus-
trative purposes only and are not to be construed as limiting the
scope of the invention thereto.
EXAMPLE I
A syrup for oral administration is prepared by combining the
following ingredients:
Ingredient (wt %)
Menthol (vapor pressure - lmm at 60'C) 0.1
Ethanol 10.0
Sucrose 45.0
Purified Water and Colorant q.s.
The above ingredients are combined to provide a solution (having
a viscosity of about 100 cps) which is then heated to a temperature of
about 60-C. 30 ml of this heated formulation are administered to an
adult human in need of treatment, thereby reducing cough and conges-
tion.
Substantially similar results are obtained when the mentholcomponent is replaced in whole or in part with acetic acid, benzoic
acid, cinnamic acid, phenylacetic acid, benzyl alcohol, borneol,
cinnamyl alcohol, citronellol, geraniol, linalool, phenylethyl al-
cohol, terpineol, anisaldehyde, cinnamaldehyde, benzaldehyde, citral,piperonal, heliotrcpin, salicylaldehyde, vanillin, carvone, camphor,
thujone, pulegone, bornyl acetate, methyl salicylate, benzyl benzoate,
geranyl acetate, linalyl acetate, thymol, carvacrol, chavicol, ane-
thole, eugenol, safrol, coumarin, indole, and mixtures thereof.
EXAMPLE II
A syrup for oral administration is prepared by combining the
following ingredients:
Menthol 0.075%
Eucalyptus Oil 0.025%
Ethanol 5.0%
Propylene Glycol 10.0%
Sucrose 40.0%
Invert Syrup 30.0%
Water and Color q.s.
- 1 1 - 2~.-117923
The abo~e ingredients are combined to provlde a solution (having
a viscosity of about 300 cps) which ls then heated to a temperature of
about 60'C. 30 ml of this heated formulation are administered to an
adult human in need of treatment, thereby reducing cough and conges-
tion.
Substantially similar results are obtained when the propylene
glycol component is replaced in whole or in part with water, simple
syrup, polyethylene glycol, alcohol, corn syrup, invert sugar, gela-
tin, ethyl oleate, cottonseed oil and sesame oil and mixtures thereof.
EXAMPEE II~
A syrup for oral administration is prepared by combining the
following ingredients:
Inaredient WtX
Menthol a. 1%
Dextromethorphan HBr O.lX
Citric Acid 0.02~o
Glycerin 10.0%
Invert Syrup (70%) 50.0%
Ethanol 5.0%
Purified Water and tolorant qs
The citric acid is dissolved in the water and ethanol at room
temperature. While stirring, the menthol, glycerin and dextromethor-
phan HBr are added to this mixture and the color is added. The invert
syrup is then added thereby producing a thick syrupy liquid (having a
viscosity of about 200 cps). The resulting syrup is then heated to
60-C. 30 ml of this heated syrup is administered to an adult human in
need of treatment, thereby reducing cough.
Substantially similar results are obtained when the dextro-
methorphan is replaced in whole or in part with a therapeutically
equivalent level of chlophedianol, carbetapentane, caramiphen, no-
scapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fomino-
ben, their pharmaceutically-acceptable salts, and mixtures thereof.
EXAMPLE IV
A suspension for oral administration is prepared by combining the
following ingredients:
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Ingredient Amount
Menthol 0.1%
Dextromethorphan HBr 0.1%
Pseudoephedrine hydrochloride 0.07%
S Microcrystalline cellulose
and sodium carboxy methyl cellulose1.25%
Sucrose 45.0%
Glycerin 5-0%
Sorbitol solution (70%) 20.0%
Potassium sorbate 0.1%
Sodium saccharin 0.2%
Purified water and Colorant q.s.
The above ingredients are combined to produce a suspension
(having a viscosity of about 350 cps), which is then heated to a
temperature of 60-C. 30 ml of this heated formulation are administer-
ed to an adult human in need of treatment, thereby reducing cough.
Substantially similar results are obtained when the dextromethor-
phan is replaced in whole or in part with a therapeutically equivalent
level of chlophedianol, carbetapentane, caramiphen, noscapine, diphen-
hydramine, codeine, hydrocodone, hydromorphone, fominoben, theirpharmaceutically-acceptable salts, and mixtures thereof.
Substantially similar results are obtained when the pseudo-
ephedrine hydrochloride is replaced in whole or in part with a thera-
peutically equivalent level of phenylpropanolamine, phenylephrine,
their pharmaceutically acceptable salts, and mixtures thereof.
WHAT IS CLAIMED IS:
