Use of phenylpropanolamine as a mucus secretogogue in the upper airways

The present invention encompasses the novel method of using .+-.phenylpropanolamine to induce mucous secretion in the upper airways of persons afflicted with sinusitis or otitis media characterized by retention of thickened respiratory secretions. These methods comprise administering to such person a safe and effective amount of .+-.phenylpropanolamine. It also encompasses certain novel oral compositions consisting essentially of l(-)-norephedrine and a pharmaceutically-acceptable excipient base.

BACKGROUND OF THE INVENTION 
This invention relates to (1) the novel method of using 
.+-.phenylpropanolamine to induce mucous secretion in the upper airways of 
persons afflicted with sinusitis or otitis media characterized by 
retention of thickened mucus and respiratory secretions and (2) certain 
novel compositions of l(-)-norephedrine and a pharmaceutically acceptable 
excipient base. 
Phenylpropanolamine is a sympathomimetic compound administered orally as an 
anorectic and as a nasal decongestant. The compound has two chiral centers 
as shown in the following structural formula (the two chiral carbons, 
labeled alpha and beta, are denoted by an asterisk): 
##STR1## 
This results in four optical isomers, listed as follows with their common 
names and absolute configurations: 
______________________________________ 
Isomer Alpha Beta 
______________________________________ 
d(+)-norephedrine S R 
l(-)-norephedrine R S 
d(+)-norpseudoephedrine 
S S 
l(-)-norpseudoephedrine 
R R 
______________________________________ 
A substance that rotates plane-polarized light in a clockwise direction is 
said to be dextrorotatory and the rotation is said to be positive. A 
substance that rotates plane polarized light in a counterclockwise 
direction is said to be levorotatory and the rotation is said to be 
negative (Solomons, Organic Chemistry, p. 246 (1978)). 
The most active isomers physiologically for known uses are those with the 
S-configuration on the beta carbon atom (Lasagna, Phenylpropanolamine--A 
Review, p.28 (1980)). These are l (-)-norephedrine 
d(+)-norpseudoephedrine. The d(+)-norpseudoephedrine isomer is a naturally 
occurring substance found primarily in the shrub Catha edulis and is used 
orally in Europe for its anorectic properties at a dose of about 40-50 
mg/day. A racemic mixture of d(+)-norephedrine and l(-)-norephedrine, 
generally referred to as either +phenylpropanolamine or 
phenylpropanolamine, is marketed as an anorectic at a dose of about 50-75 
mg/day, and as a nasal decongestant at a dose of about 75-150 mg/day. 
The four isomers of phenylpropanolamine are described in the literature. 
However, these four isomers have never been suggested to have nasal 
mucosecretory effects. For example, U.S. Pat. No. 4,818,541 issued to 
Sanderson on Apr. 4, 1989, discloses a method of inducing anorexia or 
nasal decongestion by the transdermal administration of any of the four 
isomers of phenylpropanolamine. 
Persons afflicted with sinusitis or otitis media may suffer from nasal 
congestion, eustachian tube congestion and retention of respiratory mucus. 
Many persons who suffer from sinusitis or otitis media have both upper 
respiratory congestion and retention of thickened respiratory secretions. 
Antimicrobials are used to treat the infection in sinusitis and otitis 
media while decongestants are used to treat the congestion. Medications 
that promote upper respiratory decongestion constrict blood vessels in the 
upper respiratory tract; this reduces the tissue volume and thus provides 
decongestion of congested tissues, such as tissues in the nose, eustachian 
tubes and sinuses. 
The prior art teaches that the constriction of nasal blood vessels reduces 
fluid in nasal tissues. The fluid in these tissues has two sources: (1) 
transudation which is the loss of fluid from the nasal blood vessels into 
the nasal tissues and (2) active secretion from cells in the respiratory 
mucosa and the nasal glands that secrete mucus. In healthy persons, there 
is little transudation. But transudation is increased greatly during 
infection and inflammation when the blood vessels become more permeable. 
Decongestants reduce transudation by constricting nasal blood vessels. 
Decongestants have not been considered to provide complete relief from 
nasal congestion and retention of a particular thickened respiratory 
secretion, thickened mucus, since they are not known to promote mucous 
secretion and elimination of the retained mucus. Enhanced active secretion 
of mucus from cells in the respiratory mucosa and the nasal glands that 
secrete mucus would be beneficial to a person with thickened retained 
secretions and/or infection. Increased mucous secretions would help 
liquefy any thickened retained secretions (especially in the sinuses) and 
hence facilitate their drainage. Increased mucous secretions would also 
increase the flux of antimicrobial molecules onto the mucosa to combat the 
cause of the infection. In particular, mucous secretions increase the flux 
of antibacterial molecules in the mucus that combat the cause of the 
infection and they help liquefy any thickened, retained secretions 
(especially in the sinuses) and hence facilitate their drainage. 
SUMMARY OF THE INVENTION 
It has been discovered that both l(-)-norephedrine and d(+)-norephedrine, 
alone or in combination, are active as mucosecretory agents. However, 
l(-)-norephedrine is a more potent mucus secretogogue than 
d(+)-norephedrine. 
The present invention encompasses the novel method of using 
phenylpropanolamine (defined herein as d(+)-norephedrine or 
l(-)-norephedrine or mixtures of d(+)-norephedrine and l(-)-norephedrine; 
henceforth referred to as "PPA") to induce mucous secretion in the upper 
airways of persons afflicted with sinusitis or otitis media characterized 
by retention of thickened respiratory secretions. These methods comprise 
orally administering to such person a safe and effective amount of PPA. It 
also encompasses certain novel oral compositions consisting essentially of 
l(-)-norephedrine and a pharmaceutically-acceptable excipient base. 
DESCRIPTION OF THE INVENTION 
The present invention encompasses certain novel methods and compositions 
useful for inducing mucous secretion in the upper airways of a person 
afflicted with sinusitis or otitis media characterized by retention of 
thickened respiratory secretions. Specific compounds and compositions to 
be used in the invention must, accordingly, be 
pharmaceutically-acceptable. As used herein, such a 
"pharmaceutically-acceptable" component is one that is suitable for use 
with humans without undue adverse side effects (such as toxicity, 
irritation and allergic response) commensurate with a reasonable 
benefit/risk ratio. 
METHOD OF TREATMENT 
The present invention encompasses a method of inducing mucous secretion in 
the upper airways of a human afflicted with sinusitis or otitis media 
characterized by retention of thickened respiratory secretions, comprising 
systemically administering to said subject a safe and effective amount of 
a compound selected from the group consisting of d(+)-norephedrine, 
l(-)-norephedrine and mixtures thereof. 
Sinusitis is an inflammation of the mucous membranes of the paranasal 
sinuses. It can result from inflammation caused by bacteria, allergy, 
viruses, or a closing of the sinus ostium as a result of any cause (e.g. 
change in pressure or physical obstruction). Sinusitis is usually 
classified as: (1) acute, congestive--this is the initial stage of 
inflammation/infection; (2) acute, purulent--the progression of bacterial 
infection from untreated/unresolved acute congestive form; (3) chronic, 
purulent --untreated, unresolved acute sinusitis with permanent tissue 
destruction and tissue changes. The definition of sinusitis is more fully 
described in Ballenger, Diseases of the Nose. Throat, Ear, Held and Neck, 
p. 207 (1985) and Geldman, The Principles and Practice of Rhinology, p. 89 
(1987), which are incorporated by reference herein. 
Otitis media is an inflammation of the mucous membranes of the middle ear 
cavity. As with sinusitis, it can result from bacteria, allergy, viruses, 
or a blockage of the eustachian tube from other causes (e.g. pressure 
changes or physical obstructions). Acute otitis media is the acute stage 
of infection (usually bacterial infection), with fluid or pus (purulent 
secretions) in the middle ear. Serous or secretory otitis media occurs 
when there is fluid in the middle ear cavity with no associated infection 
(i.e. the fluid is sterile). This can occur as a result of a 
non-infectious cause of eustachian tube closure, or from treated acute 
otitis media wherein fluid is retained in the middle ear. Chronic otitis 
media is the untreated/unresolved acute condition, with permanent tissue 
destruction and tissue changes. Otitis media is further described in 
Ballenger, Diseases of the Nose, Throat, Ear, Head and Neck, pp. 1113-1140 
(1985), which is incorporated by reference herein. 
The term "nasal congestion" refers to an increase in resistance to nasal 
air flow caused by increased blood volume in the nasal tissues. The term 
"upper respiratory" or "upper airways" refers to the eustachian tube and 
middle ear and the region of the respiratory tract above the larynx. This 
includes the pharynx, nasopharynx, nasal cavity (vestibule, septum, 
turbinates, olefactory region) and paranasal sinuses (sphenoid, ethmoid, 
maxillary and frontal). "Respiratory secretions" refers to any fluid 
covering the mucosa of the "upper respiratory" tract. In the nasal 
airways these respiratory secretions result mainly from active secretion 
of the components from specific secretory structures. These secretions 
also consist of protein and other substances "leaking" from the blood 
vessels onto the mucosa during inflammation of the mucosa (e.g. sinusitis, 
otitis media and rhinitis). A type of thickened respiratory secretion is 
"thickened mucus" which is mucus with abnormal physical properties 
(increased viscosity and/or elasticity). Quantitatively, thickened mucus 
has measurements within the range of 10-500 poise for apparent viscosity 
and 1-100 dynes/cm.sup.2 for elastic modulus when measured at a shear rate 
of 0.3/sec. 
The preferred techniques for measuring mucous viscoelasticity are capillary 
viscometry and magnetic microrheometry. For capillary viscometry, a small 
sample of mucus (perhaps as little as 5 microliters) is drawn into a 
capillary tube of known dimensions. Pressure (or suction) applied to the 
tube causes the mucus to flow along the tube. Flow rate at constant 
pressure, and degree of recoil when pressure is removed, are indices of 
mucous viscosity and elasticity, respectively. For magnetic 
microrheometry, a small (100-200 micrometers) iron sphere is placed into a 
mucus sample within a special chamber. This sphere is oscillated at known 
frequency by sinusoidal magnetic forces; the amplitude of oscillation is 
an index of both elastic modulus (elasticity) and loss modulus 
(viscosity). Capillary viscometry and magnetic microrheometry are further 
described in: Philippoff (W.), Han (C.D.), Barnett (B.), Dulfano (M.J.), 
"A Method for Determining the Viscoelastic Properties of Biological 
Fluids", Biorheology, pp. 55-67 (1970); Lutz (R.J.), Litt (M.), Chakrin 
(L.), "Physical-Chemical Factors in Mucus Rheology", Rheology of 
Biological Systems, H. L. Gabelnick and M. Litt (eds.), Thomas, 
Springfield, pp. 119-157 (1973), which are incorporated herein by 
reference. 
These abnormal physical properties can result from enhanced secretion of 
proteins/glycoproteins relative to water, from inflammation (influx of 
inflammatory cells, such as monocutes and neutrophils, from the blood and 
tissues), from tissue damage causing release of substances (for example, 
fibrin and DNA) that cause mucous thickening, or from mucous dehydration 
by the reabsorption of water (or through any combination of these causes). 
Typically, in this invention the dosage regimen consists of administration 
of PPA one to four times per day. Preferably, the PPA will be administered 
two to four times per day. Treatment regimens will extend for the duration 
of the sinusitis or otitis media. The PPA is preferably administered 
orally. For humans (assuming an approximate body weight of 70 kg) 
individual doses of from about 10 mg to about 100 mg of PPA are 
acceptable. Individual doses of from about 10 mg to about 50 mg are 
preferred. 
A "safe and effective amount" of PPA is an amount that is effective to 
induce mucous secretion in a human afflicted with sinusitis or otitis 
media characterized by retention of thickened mucus and respiratory 
secretions, without undue adverse side effects (such as toxicity, 
irritation, or allergic response) commensurate with a reasonable 
benefit/risk ratio when used in the manner of this invention. This 
specific "safe and effective amount" will, obviously, vary with such 
factors as the duration of treatment, the nature of concurrent therapy (if 
any), the specific dosage form to be used, the carrier employed, and the 
dosage regimen desired for the composition. As used herein, the phrase "to 
induce mucous secretion" means to either (a) produce an increase in the 
amount of mucus secreted by a person who is presently secreting mucus or 
(b) to cause mucus to be secreted by a person who is not presently 
secreting mucus. 
COMPOSITIONS 
The present invention also provides oral compositions for inducing upper 
respiratory mucous secretion consisting essentially of (a) a safe and 
effective amount of l(-)-norephedrine; and (b) a 
pharmaceutically-acceptable excipient base. 
These compositions can additionally contain a second optional compound 
selected from the following classes of compounds: non-narcotic analgesic 
non-steroidal drugs, non-narcotic analgesic non-steroidal 
anti-inflammatory drugs, antibacterials, antihistamines, antitussives or 
expectorants and combinations thereof. 
Non-narcotic analgesic non-steroidal drugs among those useful include, but 
are not limited to, acetaminophen. 
Non-narcotic analgesic non-steroidal anti-inflammatory drugs among those 
useful include, but are not limited to, the following: aspirin, 
phenacifin, indomethacin, sulindac, zomepirac, tolmefin sodium, mefenamic 
acid, meclofenamate sodium, diflunisal, flufenisal, piroxican, sudoxican, 
isoxican, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, 
fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, 
pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic 
acid, fluprofen, bucloxic acid, and pharmaceutically acceptable salts 
thereof. Preferred non-narcotic analgesic non-steroidal anti-inflammatory 
drugs are aspirin, ibuprofen and naproxen. 
Antibacterials among those useful include, but are not limited to, the 
following: cefaclor, cefadroxil, cefuroxime axetil, cephalexin, 
cephradine, cefixime, cefcanel daloxate, cefteram pivoxil, cefpodoxime, 
ampicillin, amoxicillin, bacampicillin, carbenicillin, cloxacillin, 
dicloxacillin, oxacillin, penicillin, nafcillin, lorcarbocef, 
amoxicillin+clavulanic acid, nalidixic acid, cinoxacin, oxolinic acid, 
pipemedic acid, pefloxacin, ciprofloxacin, enoxacin, temafloxacin, 
tosufloxacin, amifloxacin, lomefloxacin, ofloxacin, fleroxacin, irloxacin, 
rufloxacin, erythromycin, sulfamethizole, sulfamethoxazole, sulfisoxazole, 
tetracycline, oxytetracycline, doxycycline, trimethoprim, 
trimethoprim/sulfamethoxazole. Preferred antibacterials include: cefaclor, 
amoxicillin, amoxicillin+clavulanic acid, cefixime, ciprofloxacin, 
trimethoprim/sulfamethoxazole. 
Antihistamines among those useful include, but are not limited to, the 
following: chlorpheniramine, brompheniramine, dexchlorpheniramine, 
dexbrompheniramine, tripolidine, diphenhydramine, doxylamine, 
tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, 
phenindamine, pyrilamine, azatadine, terfenadine, astemizole, loratadine, 
acrivastine, cetirizine, azalastine, evastine, levocabastine, and 
pharmaceutically acceptable salts thereof. Preferred antihistamines 
include: chlorpheniramine, diphenhydramine, phenindamine, pyrilamine, 
terfenadine, astemizole, loratadine, acrivastine, cetirizine and 
azalastine. 
Antitussives among those useful include, but are not limited to, the 
following: dextromethorphan, codeine, terpin hydrate and pharmaceutically 
acceptable salts thereof. Preferred antitussives include: dextromethorphan 
and codeine. 
As used herein, "expectorant" does not refer to l(-)-norephedrine, 
d(+)-norephedrine, l(-)-norpseudoephedrine or d(+)-norpseudoephedrine. 
Expectorants among those useful include, but are not limited to, the 
following: guaifenesin, potassium guaicolsulfonate, potassium iodide, 
potassium citrate, iodinated glycerol, acetylcysteine, 
carboxymethylcysteine, ambroxol, sobrerol, and pharmaceutically acceptable 
salts thereof. Preferred expectorants include: guaifenesin, 
carboxymethylcysteine, iodinated glycerol, acetylcysteine, ambroxol and 
sobrerol. 
The compositions of this invention are preferably provided in unit dosage 
form. As used herein, a "unit dosage form" is a composition of this 
invention containing an amount of l(-)-norephedrine that is suitable for 
administration to a human, in a single dose, according to good medical 
practice. 
The racemic mixtures of dl-norephedrine or dl-norpseudoephedrine (in the 
form of either the free bases or the hydrochloride salts) may be separated 
from each other by fractional crystallization, taking advantage of their 
different solubilities. 
The following melting points (mp) were reported for the purified racemates 
(Hoover, F. W., & Hass, H. B., Synthesis of 2-amino-1-phenyl-1-propanol 
and Its Methylated Derivatives, J. Org. Chem., Vol. 12, pp. 506-509 
(1947)). 
______________________________________ 
dl-Norephedrine dl-Norpseudoephedrine 
______________________________________ 
Free base mp 104.degree.-105.degree. 
mp 71.degree. C. 
HCL salt mp 192.degree. C. 
mp 169.degree. C. 
______________________________________ 
Each racemic mixture can be resolved into the corresponding enantiomers by 
conversion of the amines to salts of optically pure tartaric acid (Kalm, 
M. J., "3-imidomethyloxazolidines," J. Org. Chem., Vol. 25, pp. 1929-1937 
(1960)). These salts are diastereoisomers that can be separated by 
fractional crystallization, and the amines can then be regenerated by 
treatment with alkali. The scheme shown in the figure below summarizes the 
method of resolution, using the dl-norephedrine racemate as an example. 
The separation of the racemic mixtures of dl-norephedrine or 
dl-norpseudoephedrine is more fully described in Lasagna, 
Phenylpropanolamine-A Review, p. 30, (1980), incorporated herein by 
reference. 
The following schematic describes the resolution of dl-norephedrine into 
corresponding enantiomers. 
##STR2## 
The unit dosage from will typically contain from 10 mg to 100 mg of 
l(-)-norephedrine. Preferably, the unit dosage form will be from 10 mg to 
50 mg of l(-)-norephedrine. 
The compositions of this invention may be in any of a variety of forms. 
Many different pharmaceutically-acceptable excipient bases well-known in 
the art may be used. These include, but are not limited to, solid or 
liquid fillers, diluents, co-solvents, surfactants, and encapsulating 
substances. The amount of excipient base employed in conjunction with 
l(-)norephedrine is sufficient to provide a practical quantity of material 
for administration per unit dose of the l(-)-norephedrine. Techniques and 
compositions for making dosage forms useful in the methods of this 
invention are described in the following references, all incorporated by 
reference herein: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & 
Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: 
Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd 
Edition (1976). 
The l(-)-norephedrine may be administered as an immediate release dosage 
form such as a liquid, a capsule or a tablet using an excipient base or it 
may be incorporated into a polymer excipient base to provide a long acting 
dosage form. Preferably, the excipient base or polymer excipient base 
comprises at least 50% by weight of the dose form. 
A preferred immediate release liquid comprises: 
(a) l(-)norephedrine at a level from about 0.5 to 5.0%; and 
(b) an optional active ingredient selected from the group consisting of 
non-narcotic analgesic non-steroidal anti-inflammatory drugs, non-narcotic 
analgesic non-steroidal drugs, antibacterials, analgesics, expectorants, 
antihistamines, antitussives, and combinations thereof at a level from 0% 
to 50%; and 
(c) a solvent at a level from about 50% to 95%; and 
(d) a co-solvent at a level from about 5% to 20%; and 
(e) a buffer system at a level from about 0.05% to 5%; and 
(f) a surfactant at a level from about 0.1% to 5%; and 
(g) a preservative at a level from about 0.004% to 1%; and 
(h) a sweetening agent at a level from about 0.25% to 20%; and 
(i) a flavoring agent at a level from about 0.01% to 2%; and 
(j) pharmaceutical grade dyes or pigments may be used at levels from about 
0.05% -2.0%; and 
(k) a viscosity modifier at a level from about 2% to about 15% (all 
percentages are by weight of the composition). 
A preferred solvent is water. 
Flavoring agents among those useful herein are described in the following 
reference, incorporated by reference herein: Remington's Pharmaceutical 
Sciences, 16th Edition, Mack Publishing Company, 1980, pp. 1230-1239. Dyes 
or pigments among those useful herein are described in the following 
reference, incorporated by reference herein: Handbook of Pharmaceutical 
Excipients, pp. 81-90, 1986 by the American Pharmaceutical Association & 
the Pharmaceutical Society of Great Britain. 
Preferred co-solvents are ethanol, sorbitol, glycerin, propylene glycol, 
polyethylene glycol. 
Preferred buffer systems include boric, carbonic, phosphoric, succinic, 
malic, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, 
glutaric and glutamic. Particularly preferred are phosophoric, tartaric 
and citric. 
Preferred surfactants include polyoxyethylene sorbitan fatty acid esters, 
polyoxyethylene monoalkyl ethers, sucrose monoesters and lanolin esters 
and ethers. 
Preferred preservatives are phenol, alkyl esters of parahydroxybenzoic 
acid, o-phenyl phenol benzoic acid and its salts, boric acid and its 
salts, sorbic acid and its salts, chlorbutanol, benzyl alcohol, 
thimerosal, phenylmercuric acetate and nitrate, nitromersol benzalkonium 
chloride, cetylpyridinium chloride, methyl paraben, and propyl paraben. 
Particularly preferred are salts of benzoic acid, cetylpyridinium 
chloride, methyl paraben and propyl paraben. 
Preferred sweeteners include sucrose, glucose, saccharin, aspartame. 
Particularly preferred are sucrose and saccharin. 
Preferred viscosity agents include methylcellulose, sodium 
carboxymethylcellulose, hydroxypropylmethylcellulose, carbomer, povidone, 
acacia, guar gum, xanthine gum and tragacanth. Particularly preferred are 
methylcellulose, xanthine gum, guar gum, povidone and sodium 
carboxymethylcellulose. 
A preferred immediate release capsule comprises: 
(a) l(-)-norephedrine at a level from about 2% to about 30%; and 
(b) an optional active ingredient selected from the group consisting of 
non-narcotic analgesic non-steroidal anti-inflammatory drugs, non-narcotic 
analgesic non-steroidal drugs, antibacterials, analgesics, expectorants, 
antihistamines, antitussives, and combinations thereof at a level from 0% 
to 50%; and 
(c) a filler at a level from about 20% to about 70%; and 
(d) a disintegrant at a level from about 0.1% to about 3%; and 
(e) a lubricant at a level from about 0.5% to about 6%. 
An immediate release tablet is preferably formulated in an excipient base 
that contains one or more of the components listed above for capsule 
formulation plus the following components: 
(f) a binder at a level from about 1.0% to about 10%; and 
(g) pharmaceutical grade dyes or pigments may be used at levels from about 
0.05%-2.0% (all percentages are by weight of the dose form). 
Dyes or pigments among those useful herein are described in the following 
reference, incorporated by reference herein: Handbook of Pharmaceutical 
Excipients, pp. 81-90, 1986 by the American Pharmaceutical Association & 
the Pharmaceutical Society of Great Britain. 
Preferred fillers include calcium sulfate, compressible sugar, dibasic 
calcium phosphate, starch, microcrystalline cellulose, lactose, sucrose 
and mannitol. Particularly preferred are lactose, microcrystalline 
cellulose and compressible sugar. 
Preferred disintegrants include sodium starch glycolate, croscarmellose 
sodium, crospovidone, starch, microcrystalline cellulose, alginic acid, 
soy polysaccharides, and sodium carboxymethylcellulose. Particularly 
preferred are sodium starch glycolate, crospovidone and croscarmellose 
sodium. 
Preferred binders include methylcellulose, sodium carboxymethylcellulose, 
hydroxypropylmethylcellulose, ethyl cellulose, acacia, gelatin, sucrose, 
polyvinylpyrrolidone, and guar gum. Particularly preferred are 
polyvinylpyrrolidone, methylcellulose and hydroxypropylmethylcellulose. 
Preferred lubricants include magnesium stearate, zinc stearate, calcium 
stearate, stearic acid, hydrogenated vegetable oils, glycerol 
palmitostearate, sodium lauryl sulfate, polyethylene glycol, and talc. 
Particularly preferred are magnesium stearate, zinc stearate and sodium 
lauryl sulfate. 
A preferred long acting dosage form comprises: 
(a) l(-)-norephedrine at a level from about 2% to about 20%. 
(b) an optional active ingredient selected from the group consisting of 
non-narcotic analgesic non-steroidal anti-inflammatory drugs, non-narcotic 
analgesic non-steroidal drugs, anti bacterials, expectorants, 
antihistamines, antitussives, and combinations thereof at a level from 0% 
to 20%; and 
(c) a polymer material at a level of from about 10% to about 40%; and 
(d) a lubricant at a level of from about 0.1% to about 6%; and 
(e) a filler at a level of from about 20% to about 70%; and 
(f) pharmaceutical grade dyes or pigments may be used at levels from about 
0.05% to about 2% (all percentages are by weight of the dose form). 
Preferably, the polymer material is selected from the group consisting of: 
cellulose ethers (such as methylcellulose, hydroxypropylmethylcellulose, 
hydroxypropylcellulose, and sodium carboxymethylcellulose), 
polyvinylpyrrolidone, mixtures of natural hydrophilic gums (such as guar 
gum, gum Karaya, gum tragacanth, and xanthine gum) synthetic hydrophilic 
polymers (such as carbomer) and mixtures thereof. Preferred are 
hydroxypropylmethylcellulose and mixtures of two or more cellulose ethers 
selected from the group consisting of methylcellulose, 
hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium 
carboxymethylcellulose and mixtures thereof. Particularly preferred are 
hydroxypropylmethylcellulose and carbomer. 
The lubricants, fillers, dyes and pigments are identical to those described 
for the immediate release dose form. 
The following non-limiting examples illustrate the compositions and uses of 
the present invention.

EXAMPLE I 
An immediate release tablet composition, according to the present 
invention, is made comprising the following components: 
______________________________________ 
Ingredient Per Tablet 
Percent by Weight 
______________________________________ 
1(-)-norephedrine 
37.5 mg 22.0 
hydrochloride 
Terfenadine 30.0 mg 17.6 
Lactose 65.0 mg 38.1 
Hydroxypropylmethylcellulose 
15.0 mg 8.8 
Croscarmellose sodium 
5.0 mg 2.9 
Talc 10.0 mg 5.9 
Hydrogenated castor oil 
8.0 mg 4.7 
170.5 mg 
______________________________________ 
The tablet is made by wet granulating the l(-)-norephedrine hydrochloride, 
terfenadine and the lactose with a solution of 
hydroxypropylmethylcellulose. The granulation is dried, sized and the 
remaining ingredients are sequentially dry blended and then compressed 
into tablets. 
EXAMPLE II 
An immediate release tablet composition, according to the present 
invention, is made comprising the following components: 
______________________________________ 
Percent 
Ingredient Per Tablet by Weight 
______________________________________ 
l(-)-norephedrine 37.5 mg 8.9 
hydrochloride 
Ibuprofen 200.0 mg 47.3 
Chlorpheniramine maleate 
8.0 mg 1.9 
Dextromethorphan hydrobromide 
30.0 mg 7.1 
Gelatin 7.0 mg 1.7 
Microcrystalline cellulose 
100.0 mg 23.7 
Stearic acid 15.0 mg 3.5 
Polyethylene glycol 
15.0 mg 3.5 
Calcium stearate 10.0 mg 2.4 
422.5 mg 
______________________________________ 
The tablet is made by wet granulating the l(-)-norephedrine hydrochloride, 
ibuprofen, chlorpheniramine maleate, dextromethorphan hydrobromide with a 
gelatin solution. The granulatin is dried, sized and the remaining 
ingredients are sequentially dry blended and then compressed into tablets 
on a tablet press. 
EXAMPLE III 
An immediate release capsule composition, according to the present 
invention, is made comprising the following components: 
______________________________________ 
Percent 
Ingredient Per Capsule by Weight 
______________________________________ 
l(-)-norephedrine 25 mg 19.5 
Lactose 75 mg 58.6 
Microcrystalline cellulose 
25 mg 19.5 
Magnesium stearate 
2 mg 1.6 
FD & C Yellow #6 Lake Dye 
1 mg 0.8 
128 mg 
______________________________________ 
The ingredients are sieved, sequentially dry blended and encapsulated on an 
automatic capsule filler. 
EXAMPLE IV 
An immediate release tablet composition, according to the present 
invention, is made comprising the following components: 
______________________________________ 
Ingredient Per Tablet 
Percent by Weight 
______________________________________ 
1(-)-norephedrine 
30 mg 15.8 
Dibasic calcium phosphate 
125 mg 65.8 
Crospovidone 5 mg 2.6 
Microcrystalline cellulose 
25 mg 13.2 
Zinc stearate 5 mg 2.6 
190 mg 
______________________________________ 
The ingredients are sieved, sequentially dry blended and compressed into 
tablets on a tablet press. 
EXAMPLE V 
An immediate release chewable tablet composition, according to the present 
invention, is made comprising the following components: 
______________________________________ 
Percent 
Ingredient Per Tablet by Weight 
______________________________________ 
l(-)-norephedrine 37.5 mg 5.7 
Sucrose (granular) 300.0 mg 45.3 
Mannitol (granular) 
300.0 mg 45.3 
Sodium carboxymethylcellulose 
10.0 mg 1.5 
Sodium lauryl sulfate 
6.0 mg 0.9 
Stearic acid 9.0 mg 1.3 
662.5 mg 
______________________________________ 
The ingredients are sieved, sequentially dry blended and compressed into 
tablets on a tablet press. 
EXAMPLE XII 
A thirty-five-year-old woman afflicted with sinusitis that is characterized 
by upper respiratory congestion and retention of thickened mucus and other 
thickened respiratory secretions is given a tablet formulated as in 
Example X four times a day. Administration of the above tablet results in 
decongestion and the drainage of mucus and respiratory secretions. 
EXAMPLE XIII 
A twenty-five-year-old man afflicted with sinusitis that is characterized 
by retention of thickened mucus and other thickened respiratory secretions 
is given a tablet formulated as in Example X four times a day. 
Administration of the above tablet results in the drainage of mucus and 
other respiratory secretions. 
EXAMPLE XIV 
A ten-year-old child afflicted with otitis media that is characterized by 
eustachian tube congestion and retention of thickened respiratory 
secretions, especially thickened mucus, is given a capsule formulated as 
in Example III four times a day. Administration of the above capsule 
results in the drainage of the mucus and other respiratory secretions. 
EXAMPLE XV 
A forty-three-year-old man afflicted with sinusitis characterized by 
retention of thickened respiratory secretions, especially thickened mucus, 
is given a tablet formulated as in Example V three times a day. 
Administration of the above tablet results in the drainage of mucus and 
other respiratory secretions. 
EXAMPLE XVI 
A thirty-seven year old man suffering from a persistent cough, postnasal 
drip and retention of thickened nasal and sinus mucus and other 
respiratory secretions is orally given a tablet formulated as in Example 
VI two times a day. Administration of the above tablet results in 
suppression of the persistent cough and drainage of the retained mucus and 
other respiratory secretions. 
EXAMPLE VI 
A long acting dosage composition, according to the present invention, is 
made comprising the following components: 
______________________________________ 
Percent 
Ingredient Per Unit Dose 
by Weight 
______________________________________ 
l(-)-norephedrine 
50.0 mg 11.6 
Compressible sugar 
250.0 mg 57.8 
Carbomer 100.0 mg 23.1 
Stearic acid 20.0 mg 4.6 
Zinc stearate 6.0 mg 1.4 
FD & C Blue #2 Lake Dye 
6.5 mg 1.5 
432.5 mg 
______________________________________ 
The l(-)-norephedrine, compressible sugar, carbomer, stearic acid, and FD&C 
Yellow #6 Lake Dye are roller compacted, sized and the zinc stearate is 
then dry blended and tablets are then compressed on a tablet press. 
EXAMPLE VII 
A long acting dosage composition, according to the present invention, is 
made comprising the following components: 
______________________________________ 
Percent 
Ingredient Per Unit Dose 
by Weight 
______________________________________ 
l(-)-norephedrine 50 mg 10.5 
Hydroxypropylmethylcellulose 
175 mg 36.8 
Lactose 225 mg 47.4 
Talc 15 mg 3.2 
Magnesium stearate 
10 mg 2.1 
475 mg 
______________________________________ 
The l(-)-norephedrine and lactose are wet granulated with one third of the 
hydroxypropylmethylcellulose, dried and then sized. The remaining 
ingredients are sequentially dry blended and compressed on a tablet press. 
EXAMPLE VIII 
A long acting dosage composition, according to the present invention, is 
made comprising the following components: 
______________________________________ 
Ingredient Per Unit Dose 
Percent by Weight 
______________________________________ 
l(-)-norephedrine 
40 mg 7.3 
Hydroxypropylcellulose 
150 mg 27.1 
Sucrose 225 mg 40.7 
Dibasic calcium phosphate 
100 mg 18.1 
Sodium lauryl sulfate 
15 mg 2.7 
Hydrogenated castor oil 
15 mg 2.7 
FD & C Blue #2 Dye 
8 mg 1.4 
553 mg 
______________________________________ 
All the ingredients are sized, sequentially dry blended and compressed into 
tablets on a tablet press. 
EXAMPLE IX 
An immediate release liquid dosage composition, according to the present 
invention, is made comprising the following components: 
______________________________________ 
Ingredient Per Liter 
Percent (wt./volume) 
______________________________________ 
Purified Water 400.0 g -- 
l(-) norephedrine 
2.0 g 0.2 
Citric Acid, anhydrous 
1.2 g 0.12 
Sodium Benzoate 1.2 g 0.12 
Sodium Chloride 5.3 g 0.53 
Sodium Saccharin 
2.5 g 0.25 
Sucrose 120.0 g 12.0 
Sorbitol Solution 
450.0 g 45.0 
Glycerin 60.0 g 6.0 
Mixed Fruit Flavor 
8.0 g 0.8 
(Natural & Artificial) 
FD & C yellow No. 6 
0.1 g 0.01 
Purified Water quantum 
-- -- 
sufficient(Q.S.) to one liter 
______________________________________ 
The purified water is warmed and the l(-)-norephedrine, citric acid 
anhydrous, sodium benzoate, sodium chloride, sodium saccharin, sucrose, 
and FD&C yellow No. 6 are dissolved. The solution is cooled and the 
sorbitol solution, glycerin, mixed fruit flavor and a sufficient quantity 
of purified water are added to make one liter of the immediate release 
liquid composition. 
One teaspoonful (5 cc) contains 10 mg of l(-) norephedrine. 
EXAMPLE X 
An immediate release dosage composition, for use according to the present 
invention, is made comprising the following components: 
______________________________________ 
Ingredient Per Tablet 
Percent by Weight 
______________________________________ 
(racemic mixture of d(+)- 
37.5 mg 9.9 
norephedrine and l(-) 
norephedrine)HCl 
Microcrystalline cellulose 
100.0 mg 26.5 
Compressible sugar 
200.0 mg 53.0 
Sodium starch glycolate 
10.0 mg 2.6 
Stearic acid 15.0 mg 4.0 
Talc 15.0 mg 4.0 
377.5 mg 
______________________________________ 
All the ingredients are sized, dry blended and compressed into tablets on a 
tablet press. 
EXAMPLE XI 
A long acting release dosage composition, for use according to the present 
invention, is made comprising the following ingredients: 
______________________________________ 
Ingredient Per Tablet 
Percent by Weight 
______________________________________ 
Guaifenesin 400 mg 51.3 
(racemic mixture of d(+)- 
75 mg 9.6 
norephedrine and l(-)- 
norephedrine)HCl 
Carbomer 117 mg 15.0 
FD & C Blue #1 Aluminum 
3 mg 0.4 
Lake Dye 
Compressible Sugar 
139 mg 17.8 
Stearic Acid 40 mg 5.1 
Zinc Stearate 6 mg 0.8 
780 mg 
______________________________________ 
The guaifenesin, (racemic mixture of d(+)-norephedrine and 
l(-)-norephedrine) HCl, carbomer, dye and stearic acid are roller 
compacted and sized. The compressible sugar and zinc stearate are added 
and then compressed into tablets on a tablet press. 
EXAMPLE XVII 
A forty-four-year-old man suffering from nasal and sinus congestion and 
retention of thickened mucus and other respiratory secretions is orally 
given a tablet of 75 mg of a composition containing l(-)-norephedrine and 
guaifenesin twice a day. Administration of the above tablet results in 
nasal and sinus decongestion and drainage of the retained mucus and other 
respiratory secretions. 
EXAMPLE XVIII 
A three-year-old child afflicted with otitis media that is characterized by 
eustachian tube congestion and retention of thickened respiratory 
secretions, especially thickened mucus, is given a half teaspoon of the 
formulation of Example IX four times a day. Administration of the above 
liquid results in the drainage of the mucus and other respiratory 
secretions.