PT97730A - METHOD FOR PREPARING A ORAL COMPOSITION CONTAINING NOREFEDRINE FOR THE TREATMENT OF SINUSITE OR OTITE MEDIA - Google Patents

Description

1 10 15

Mod. 71-20,000 e *. - 9O | 0B 20 25 63474 Case N544

This invention relates to a novel process for the use of phenylpropanolamine to induce mucosal secretion in the upper respiratory tract of persons suffering from sinusitis or otitis media, characterized by the retention of thick mucus and respiratory secretions? and also relates to (2) certain novel 1-norephedrine compositions 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 can be seen in the following structural formula (the two chiral carbons, termed alpha and beta, are marked with an asterisk)!

-CH 2 -CH 2 -CH 2 -CH 2 -

Thus, four optical isomers listed, with their common names and absolute configurations, are obtained as follows:

Alpha Isomer Beta 30

d (+) - norephedrine S R

1 (-) - norephedrine R S

d (+) - norpseudoephedrine S S

1 (-) - norpseudoephedrine R R 35 1 5 10

15

Mod. 71 -10000 ex. - 89/07

25 30 63474 Case N544

A substance which causes rotation of polarized light in a plane in a clockwise direction is said to be dextrorotatory, and rotation is positive. A substance which causes rotation of plane-polarized light in a counter-clockwise direction is said to be photometric and negative rotation (Solomons, Organic Chemistry, page 246 (1978)). Most physiologically active isomers for known uses are those having an S-configuration on the beta carbon atom (Lasagna, Phenylpropanolamine-A Review, page 28 (1980)). These are 1 (+) - norephedrine and d (+) - norpseudoephedrine. The d (+) - norpseudoephedrine isomer is a natural substance which is found essentially in " Catha edulis " and which is used orally in Europe for its anorectic properties at a dose of about 40-50 mg / day. A racemic mixture of d (+) - norphedrine and 1 (-) - norephedrine, generally referred to as + phenylpropanolamine or phenylpropanolamine , is marketed as anorectic, at a dose of about 50-75 mg / day, and as nasal decongestants at a dose of about 75-150 mg / day. Phenylpropanolamine quaternary amines are described in the literature. However, it has never been suggested that these four isomers had nasal mucosecretory effects. For example, U.S. Patent 4,818,541, Sanderson, issued April 4, 1989, discloses a method for inducing anorexia or nasal decongestion by transdermal administration of any of the four isomers of phenylpropanolamine. People with sinusitis or otitis media may suffer from nasal congestion, tube congestion of " Eustachian " and retention of respiratory mucus. Many people with sinusitis or otitis media suffer from both upper respiratory tract congestion and secretion retention - 2 - 35 1 5 10) 15

Mod. 71 -10000 ex. - 89/07 20 > 25 30 63474 Case N544

respiratory infections. Antimicrobial agents are used in treatment, sinusitis infection and otitis media, and decongestants in the treatment of congestion. Are medications that cause upper airway decongestion to constrict blood vessels in the upper respiratory tract? which reduces the volume of tissues, causing the congestion of congested tissues, such as tissues in the nose, Eustachian tubes and sinuses. Prior art has shown that constriction of the nasal blood vessels reduces fluid in the nasal tissues. The fluid in these tissues has two origins: (i) transudation, which is the loss of fluid from the nasal blood vessels to the nasal tissues, and (2) active secretion of the respiratory mucosa cells and nasal glands that secrete mucus. there is little transudation, but transudation increases greatly during infection and inflammation as the blood vessels become more permeable.Decongestants decrease transudation by contortion of the nasal blood vessels. nasal congestion and retention of particularly thick respiratory secretions, thick mucus, since, as far as is known, they do not ensure the secretion of the mucous membranes and the elimination of the retained mucus.The increase in the active secretion of mucus from the respiratory mucosa cells and of the nasal glands that secrete mucus would be beneficial for a person who retains secretions. and / or had an infection. Increased mucus secretions would help liquefy any thick secretions retained (especially in the sinuses) and thereby facilitate their drainage. The increase in mucous secretions would also increase the flow of antimicrobial agent molecules to the mucosa to counteract the cause of the disease. 15 63474 Case N544

Mod. 71 -10000 ex. Infection. In particular, mucus secretions increase the mucus flow of the antibacterial molecules that fight the infection's causation, and help to liquefy which thick secretions retained (especially in the sinuses), thereby facilitating and draining them. Summary of the Invention It has been found that both 1 (-) - norephedrine and ad (+) - norephedrine, alone or in combination, are active as mucosecretory agents. However, 1 (-) - norephedrine is a more potent mucus secreting agent The present invention provides a novel method of using phenylpropanolamine (defined herein as d (+) - norephedrine or 1 (-) - norephedrine or mixtures of di + - norephedrine and 1 (+) - norephedrine. These methods comprise the oral administration to that person of a safe and effective amount of a compound of formula (I) in the form of a compound of formula (I). The invention also relates to certain novel oral compositions consisting essentially of 1 (-) - norephedrine and a pharmaceutically acceptable excipient base. and innovative compositions and compositions useful for the induction of secretions of mucus in the upper respiratory passages of someone with sinusitis or otitis media, characterized by the retention of thick respiratory secretions. The specific compounds and compositions to be used in this invention should therefore be pharmacologically acceptable. For the purposes of this invention, a pharmaceutically acceptable component is a suitable component for use in humans without adverse side effects such as toxicity, irritation and /

Mod. 71 -10000 ex. - 89/07 20

30 63474 Case N544 allergic response) within a benefit / risk.

The present invention relates to a method for inducing mucous secretions in the upper respiratory tract of a human being afflicted with sinusitis or otitis media characterized by the retention of thick respiratory secretions, which method comprises administering systemic to said subject, a safe and effective amount of a compound selected from the group consisting of d (+) - norephedrine, 1 (-) - norephedrine and mixtures thereof. Sinusitis is an inflammation of the mucous membranes of the paranasal sinuses It may result from an inflammation caused by bacterial allergy or virus, or from the closure of the "sinus ostium" caused by any cause (eg, pressure change or physical obstruction). Is this the initial phase of inflammation / infection? (2) Acute, purulent - progression from bacterial infection to pa acute uncontrolled / unresolved congestive form? (3) -chronic, untreated and unresolved acute purulent-sinusitis with permanent destruction of tissues and modification of tissues. The definition of sinusitis is described more fully by Ballenger in Diseases of the Nose, Throat, Ear, Head and Neck, page 207 (1985) and Geldman, The Principles and Practice of Rhinology, page 89 ¢ 1987), which are incorporated by reference. Otitis media is an inflammation of the mucous membranes of the middle ear cavity. Like sinusitis, it can result from bacteria, allergies, viruses, or Eustachian tube blockage from other causes (eg, pressure changes or physical obstructions). Acute otitis media is the state of acute infection (usually - 5 - 35 1 5 10 15

Mod. 71-10000 ex. - 89/07 20

30 63474 Case N544

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 without there being an associated infection (i.e., the fluid is sterile). This may be due to a noninfectious cause that closes the Eustachian tube, or a treated acute otitis media in which fluid is retained in the middle ear. Chronic otitis media is the acute untreated / unresolved condition, with permanent tissue destruction and tissue alteration. Otitis media is described in more detail by Ballenger in Diseases of the Nose, Throat, Ear, Head and Neck, pages 1113-1140 (1985), incorporated herein by reference. □ term " nasal congestion " refers to an increase in resistance to nasal airflow, caused by increased blood volume in the nasal tissues. The term " upper respiratory tract " refers to the Eustachian tube and middle ear, is the region of the respiratory tract above the larynx. This includes the pharynx, nasopharynx, nasal cavity (vestibule, septum, turbinates, olfactory region) and paranasal sinuses (ethoside, ethmoid, maxillary and frontal sinuses). The term " respiratory secretions " refers to any fluid that covers the mucosa of the upper respiratory tract ". In the nasal passages, these respiratory secretions essentially result from the active secretion of the components from specific secretory structures. These secretes are also made up of proteins and other substances that "escape" of the blood vessels to the mucosa during inflammation of the mucosa (eg sinusitis, otitis media and rhinitis). One type of thick respiratory secretion is the " thick mucus " which is a mucus with abnormal physical properties (increase in viscosity and / or elasticity). Quantitatively, the thick mucus presents measures between 10 - 500 Poise for a - 6 - 35 1 5. 10 15

Mod. 71-10000 ex. - 89/07 > 25 30 63474 Case N544

apparent viscosity and 1-100 dynes / cmS for the elastic modulus when measured at a shear rate of 0.3 / sec. Preferred techniques for measurement of mucus viscoelasticity are capillary viscometry and magnetic microreometry. For capillary viscometry, only a small sample of mucus (perhaps 5 microlites) is placed in a capillary tube of known dimensions. Pressure (or suction) is applied to the tube, which causes the mucus to flow along the tube. The flow rate measured at constant pressure and the degree of recoil when removing the pressure are, respectively, indices of the viscosity and elasticity of the mucus.

For magnetic microreometry, a small steel sphere (100-200 micrometers) is placed inside a specimen of mucus placed in a special chamber. Does this wait suffer from oscillations of frequency known by the effect of sinusoidal magnetic forces? the amplitude of oscillation a) an index of both the elastic modulus (elasticity) and the modulus of loss (viscoelasticity). Capillary viscometry and magnetic microreometry are described in more detail in Philippoff (W.) Han (CD > Barnett (B > Dulfano (MJ), " A Method for Determining the Viscoelastic Properties of Biological Fluids " , Biorheoloqy, pages 55-67 (1970) Lutz (RJ), Litt (M.), Chakrift (L), " Phvsical-Chemical Factors in Mucus Rheology ", Rheoloav of Ethiopical Systems, edited by HL Gabelnick and M.Litt, Thomas, Springfield, pages 119-157 (1973) incorporated herein by reference.

These abnormal physical properties may result from increased protein / glycoprotein secretion to water, from inflammation (influx of inflammatory cells), such as monocytes and neutrophils, from the blood and from the blood. woven fabrics), - 7 - 35 1 5 10 > 15

Mod. 71 -10000 ex. - Cass N544 89/07 20 25 30 63474

(eg, fabrina and DNA) causing mucus thickening, or dehydration of mucus caused by water reabsorption (or any combination of these causes). Typically, in this invention the dosage regimen consists of the administration of PPA one to four times per day. Preferably, the PPA should be administered two to four times a day. Treatment regimens should be maintained for the duration of sinusitis or otitis media. PPA is preferably administered orally. For humans (weighing approximately 70 kg), individual doses of about 10 mg to about 100 mg of PPA are acceptable. Dosages of about 10 mg to about 50 mg are preferred. A " safe and effective amount " of PPA is the amount capable of inducing mucus secretion in a human with sinusitis or otitis media characterized by retention of thick mucus and respiratory secretions without adverse side effects (such as toxicity, irritation, or allergic response), while maintaining a reasonable benefit / risk ratio, when used in accordance with this invention. Obviously, the effectiveness and safety of the drug varies, of course, with factors such as the duration of the treatment, the nature of any possible simultaneous therapy, the specific form of the dosage used, the carrier agent used, and the regimen the desired dosage for the composition. For the purposes of this disclosure, the phrase " induce mucus secretion " means either (a) to produce an increase in the amount of mucus secreted by a person who is currently secreting mucus, (b) to cause mucus secretion by a person who does not segregate it at the moment. The present invention also relates to oral compositions for inducing secretion of mucus from the upper airways, consisting essentially of

a) a safe and effective amount of 1 < -) - norfedrine;

Mod. 71 -10000 ex. B) a pharmaceutically acceptable excipient base. These compositions may additionally contain a second optional compound selected from the following classes of compounds: non-narcotic and non-steroidal analgesic drugs, non-narcotic analgesic drugs and non-steroidal anti-inflammatory, antibacterial, antihistaminic, antitussive or expectorant drugs and combinations thereof. Useful non-narcotic and non-stereochemical analgesic drugs include, but are not limited to, acetaminophen. Useful non-narcotic analgesic and antiinflammatory drugs include, but are not limited to, the following: aspirin, phenazepine, indomethacin, sulindace, zomepirace, sodium tolmefine, mefenamic acid, meclofenamate sodium, diflunisal, flufenisal, piroxicane, sudoxicane , isoxicane, ibuprofen, naproxen, benoxaprofen, flurbiprofen, penoprofen, penbufene, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozine, pranoprofen, myroprofen, thioxaprofen, suprofen, alminoprofen, thiaprofenic acid, fluprofen, blucloxic acid, and pharmaceutically acceptable salts thereof. Non-narcotic analgesic and non-steroidal anti-inflammatory drugs are aspirin, ibuprofen and naproxen. Useful antibacterial agents include, but are not limited to, the following: cefaclor, cefadroxil, cefuroxime, axetil, cefalexine, cefradine, cefixine, cefexel daloxate, cefteram pivoxil, cefpodoxine, ampicillin, amoxycycline, bacampycin, carbenicillin, cloxacillin, dicloxacillin, oxacillin, penicillin, nafcillin, lorcarboceph, amoxicillin + clavulanic acid, nalidixic acid, cinoxacin, oxolinic acid, - 9 - 35

63474 Case N544 ofloxacine, erythromycin, sulfisoxazole, trimethoprim, antibacterial pipemedic acid, pefloxacin, ciprofloxacin, eno; acine, temafloxacine, tosufloxacine, amifloxacin, lomefloxacin, fleroxacin, irlaxacin, rufloxacin, sulfamethoxazole, sulfamethoxazole, tetracycline, oxytetracycline, doxycycline, trimethoprim / sulfamethoxazole. Preferred agents include: cefaclor, amoxicillin, amoxicillin + clavulanic acid, cefixime, ciprofloxacin, trimethoprim / sulfamethoxazole.

Useful antihistamines include but are not limited to the following; chlorpheniramine, bromopheniramine, dexchlorpheniramine, dexbromopheniramine, tripolidine, diphenhydramine, doxylamine, tripelenamine, cyproheptadine, carbinoxarine, bromodiphenhydramine, phenindamine, pyrilamine, azatadine, terfenadine, astemizole, loratadine, acrivastine, cetirizine, azalastine, evastine, levocabastine, and pharmaceutically acceptable salts thereof. Preferred antihistamines include; chlorpheniramine, diphenhydramine, fenindamine, pyrimidine, terfenadine, astemizole, loratadine, acrivastine, cetirizine and azalastine.

Useful antitoxins include, but are not limited to, the following: dextromethorphan, codeine, terfine hydrate and pharmaceutically acceptable salts thereof. Preferred antitussives include: dextromethorphan and codeine.

For the purposes of this specification, the term " expectorant " does not refer to 1 (-) - norephedrine, d (+) - norephedrine, 1 (-) - norpseudoephedrine or d (+) - norpseudoephedrine. Useful expectorants include, but are not limited to, the following: guaifenesine, potassium guaicolsulfonate, potassium iodide, potassium citrate, iodinated glycerol, acetylcysteine, carboxymethylcysteine, ambroxol, sobrerol,

Mod. 71 -10000 ex. - 89/07 20 25 63474 Case N544

And pharmaceutically acceptable salts thereof. Preferred expectorants include: guaifenesine, carboxymethylcysteine, iodinated glycerol, acetylcysteine, ambroxol and sobrerol. The compositions of this invention are preferably presented in unit dosage form. For the purposes of this specification, the term " unit dosage form " means a composition of this invention containing an amount of 1 (-) - norephedrine which is suitable for administration to humans in a single dose, in accordance with good medical practice. Racemic mixtures of dl-norephedrine or dl-norpseudoephedrine (either in the form of free bases or of hydrochloride salts) may be separated by fractional crystallization, taking advantage of their different solubilities. The following melting points (mp) were reported for the purified racemates (Hoover, FW, & Hass, HB, " Synthesis of 2-amino-1-phenyl-1-propanol and it's Methylated Derivatives ", J. Org. Chem., Vol. 12, pp. 306-509 (1947)).

Dl-Norephedrine 0 o Free Base m.p.104-105 C HCl salt m.p. 192 ° C

Dl-Nordoudoephedrine m.p. 71 ° C, m.p. 169 ° C

Each racemic mixture can be transformed into the corresponding enantiomers by conversion of the amines to salts of optically pure tartaric acid (Kalm, M. J., " 3-imidomethyloxazolidines ", J.Chem., 30

Vol. 25, pages 1929-1937 (1960)). These salts are diastereoisomers which can be separated by fractional crystallization, and the amines can be renegered by treatment with bases. The scheme, shown in the following figure summarizes the resolution method, using the dl-norephedrine racemate as an example. The separation of the mixtures - 11 - 35

63474 Racemic case N544 of dl-norephedrine or dl-norpseudoephedrine is

Lasagna, as described in more detail Phenylpropanolamine - A Review, p. 30, (1980) incorporated herein by reference. The following scheme describes the resolution of dl-norephedrine in the corresponding enantiomers.

dl-norephedrine m.p. 104 ° C 10

Mod. 71 -10000 ex. D-tartaric acid in methanol

D-norephedrine-d-bitartrate salt 1-norephedrine-dHbitartrate salt crystallizes

NaOH d-norephedrine

D m.p. 5H C + 14.0 * remains in solution

NaOH

1-norephedrine m.p. 50.0 ° C = -14.5 ° D The unit dosage form typically contains from 10 mg to 100 mg of 1 (-) - norephedrine. Preferably, the unit dosage form is from 10 mg to 50 mg of 1-norephedrine. 30

The compositions of this invention may be in various forms. Various pharmaceutically acceptable and well-known bases and agents may be used in the medium. These starting bases include, but are not limited to, solid fillers or liquid diluents, cosolvents, surfactants and encapsulating substances. The amount of excipient base employed 12 - 35 10 15

Mod. 71 -10000 ex. - 89/07 20 25 30 63474 Case N544

together with 1 (-) - norephedrine is sufficient to give a practical amount of substance for unit dose administration of 1 (-) - norephedrine. Techniques and compositions for producing dosage forms useful in the processes of this invention are described in the following documents, incorporated herein by reference; 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, eds., 1979)? Lieberman et al., Pharmaceutical Dosaoe Formsa Tablets (1981); and Ansel, Introduction to Pharmaceutical

Dosaqe Forms, Hâ € ™ edition (1976). Narephedrine can be administered in an immediate release dosage form, such as a liquid, a capsule or a tablet, using an excipient base, or may be incorporated into a polymeric excipient base to give a form dosing system. Preferably, the excipient base or polymeric excipient base comprises at least 50% by weight of the dosage form. A preferred immediate release liquid is comprised of: a) 1 (-) - narephedrine in a content of about 0.5 to 50%; and b) an optional active ingredient selected from the group consisting of non-narcotic anti-inflammatory non-steroidal analgesic drugs, non-narcotic and non-steroidal analgesic drugs, antibacterials, analgesics, expectorants, antihistamines, antitussives, and combinations thereof , in a content from 0% to 50%, c) one d) one e) one 5%; and f) 5%; and * 3 > a f) a surfactant, in a content of about 0.1% to g) a preservative, in a content of about 0.004% to 1%; (h) a sweetening agent, at a

Invention are 207. and i) a flavoring agent, in a content of about 0.001% to 2%, and paints or pigments which may be used in amounts of about 0.005% - 2.0%? and k) a viscosity modifying agent at a high content. 2% about 15% < all percentages are by weight of the composition) The preferred solvent is water.

Useful flavoring agents are described in the following document incorporated herein by reference; Reminqton's Farmaceutical

Sciences, 16th Edition, Mack Publishing Company, 1980, pages 15

Mod. 71 -10000 ex. - 89/07 20 1230-1239. Paints or pigments useful in this invention are described in the following document incorporated herein by reference! Handbook of Pharmaceutical Excipients, pages 81-90, 1986, of the " American Pharmaceutical Association " and the " Pharmaceutical Society of Great Britain ". Preferred co-solvents are ethanol, sorbitol glycerin, propylene glycol and polyethylene glycol. > 25 30

Preferred buffer systems include boric, carbodic, phosphoric, succinic, malic, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric and glutamic. Particularly preferred are phosphoric, tartaric and citric systems.

Preferred surface active agents include polyoxyethylene sorbitan fatty acid esters, polyoxyethylene ethers, monoalkyl, sucrose monoester esters and lanolin ethers.

Preferred preservatives are phenol, alkyl esters of parahydroxybenzoic acid, o-phenyl phenol benzoic acid and their salts, boric acid and its salts,

Mod. 71 -10000 ex. - 89/07 20 25 63474 Case N544

Sulfobarboxylic acid and its salts, chlorobenzyl, benzyl alcohol, thimerosol, phenylmercuric acetate and nitrate, nitromersol benzalkonium chloride, cetylpyridinium chloride, methylparaben and propyl paraben. Particularly preferred are the salts of benzoic acid, cetylpyridinium chloride, methyl paraben and propyl paraben.

Preferred sweeteners include sucrose, glucose, saccharin and aspartame. Particularly preferred are sucrose and saccharine. Preferred viscosity modifying agents include methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, carbomer, povidone, acacia, guar gum, canteen and tragacanth. Particularly preferred are methylcellulose, xanthan gum, guar gum, povidone and sodium carboxymethylcellulose. A preferred immediate release capsule comprises: a) 1 (-) - norephedrine, in a content of about 2% to about 30%; and b) an optional active agent selected from the group consisting of non-narcotic analgesic non-steroidal anti-inflammatory drugs, non-narcotic and non-steroidal analgesic drugs, antibacterials, analgesics, expectorants, antihistamines, anti-tics, and combinations thereof , in an amount of about 07 to 50%; and c) a filler having contents of about 207 and about 70%? and d) a disintegrating agent in amounts of from about 0.1% to about 3%; and e) a lubricating agent, in amounts of about 0.5 to about 6%.

An immediate release tablet is preferably formulated in an excipient base containing one or more of the components listed above for the capsule formulation, in addition to the following components:

Mod. 71-10000 ex.-89/07 20 25 30 63474 Case N544

f) a binder, in a content from about 1.0% to about 10%; and g) pharmaceutical inks or pigments, which may be used in amounts of about 0.05% -2.0% (all percentages are by weight of the dosage form), Paints or pigments suitable for this invention are described in the following document , incorporated herein by reference; Handbook of Pharmaceutical Excipients, pages 81-90, 1986, from the American Pharmaceutical Association " 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 disintegrating agents include sodium starch glycolate, croscarmellose sodium, crospovidone, starch, microscrystalline 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, ethylcellulose, acacia, gelatin, sucrose, polyvinylpyrrolidone, and guar gum. Particularly preferred are polyvinylpyrrolidone, methylcellulose and hydroxypropylmethylcellulose. Preferred lubricating agents 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, sinte stearate and sodium lauryl sulfate. 16 - 35 i 5 10 15

Mod. 71-10000 ex. -89/07 20 25 30 63474 Case N544 \ 21-MAUSil

A preferred dosage consisting of (a) 1 -) - norephedrine, in an extended action content of about 2% to 5, of about 207; (b) an optional active ingredient selected from the group consisting of non-narcotic analgesic non-steroidal anti-inflammatory drugs, non-narcotic non-narcotic analgesic drugs, antibacterial agents, expectorants, antihistamines, anti-tics, and combinations thereof, in a content of 0% to 20%; and (c) a polymeric material, in a content of about 10% to 40%; and (d) a lubricant, in a content from about 0.1% to about 6%; and <e) a filler, in a content from about 20% to about 70%; and (f) pharmaceutical paints or pigments, which may be used in amounts of about 0.05% to about 2% (all percentages are by weight of the dosage form). Preferably, the polymeric 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 karavan, gum tragacanth, and xanthan gum), hydrophilic synthetic 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. Lubricants, fillers, 35 - 17 - 63474 Case N544

2 /

Ingredients 1 inks and pigments are identical to those previously described for immediate-release dosage forms.

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 from the following components

Per Pill Percent Weight 15

Mod. 71-10000 ex. - 89/07 20

1 &lt; - &gt; -Naphthalene hydrochloride 37.5 mg 22.0 Terfenadine 30.0 mg 17.6 Lactose 65.0 mg 38.1 Hydroxypropylmethylcellulose 15.0 mg 8.8 Croscarmellose sodium 5.0 mg 2 , 10.0 mg 5.9 hydrogenated castor oil 8.0 mg 4.7 170.5 The tablet is made by wet granulating the 1 (-) - norephedrine hydrochloride, terfenadine and lactose with a solution of hydroxypropylmethylcellulose. The granulate is dried, sized and the remaining ingredients are sequentially dried, sequentially, and then compressed to give tablets.

Example II

An immediate release tablet composition according to the present invention is comprised of the following components; 18 - 35

63474 Case N544

Ingestants Per Tablet Percentile In Weight 1 <-> - Narephedrine Hydrochloride 37.5 mg 8.9 Ibuprofen 200.0 mg 47.3 Chlorpheniramine maleate S, 0 mg 1.9 Dextromethorphan hydrobromide 30.0 mg 7.1 Gelatin 7, 0 mg 1.7 Microcrystalline cellulose 100.0 mg 23.7 4 stearic acid 15.0 mg 3.5 polyethylene glycol 15.0 mg 3.5 Calcium stearate 10.0 mg 2.4 422.5 mg

Mod. 71-10000 ex. The tablet is made by wet granulating the 1-hydroxyethrin hydrochloride, ibuprofen, chlorpheniramine maleate and dextromethorphan hydrobromide with a solution of gelatin. The granulate is dried, suitably sized. The remaining ingredients are sequentially dry blended, and thereafter are subjected to compression in a tablet press to give the tablets Exemolo III An immediate release capsule composition according to the present invention is constituted by the following components Ingredients Per Capsule Percent by Weight Π - 25 mg 19.5 30 Lactose 75 mg 58.6 Microcrystalline cellulose 25 mg 19.5 Magnesium stearate 2 mg 1.6 Yellow pigment FD &amp; C Yellow # 6 Lake 1 mg 0.8 35 128 mg - 19

Ingredients 10

Mod. 71-10000 ex. - 89/07 63474 Case N544

The ingredients are sifted, sequentially blended and encapsulated in an automatic capsule filler.

Example IV

An immediate release tablet composition according to the present invention comprises the following components

Per Tablet Weight Percent 1 &lt; ~) -norephedrine 30 mg 15.8 Calabibasic Calcium Phosphate 125 mg 65.8 Crospovidone 5 mg 2.6 Microcrystalline Cellulose 25 mg 13.2 15 Zinc Stearate 5 mg 2.6 190 mg 20 dry blended in a tablet press.

The ingredients are sieved, sequentially and, compressed into tablets, to give

Example V

An immediate release chewable tablet composition according to the present invention consists of the following components:

Ingredients

Per Tablet Percent Weight 30 1 ("> Norephedrine Sucrose (granular> Hanitol (granular) Garboxymethylcellulose 37.5 mg 300.0 mg 300.0 mg sodium 10.0 mg 5.7 45.3 45.3 1.5 - 20 - 35

I

1.3 6.0 mg 9.0 mg 662.5 mg

Mod. 71-10000 ex. - 89/07 63474 Case N544 1 Sodium Lauryl Sulfate Stearic Acid

The ingredients are sieved, dry blending sequentially and subjected to compression in a tablet press to produce the tablets.

Example VI

An extended-acting dosage composition according to the present invention is comprised of the following components:

Ingredients Per Unit Dose Percentaqem 1 (-) - norephedrine 50.0 mg 11.6 Compressible sugar 250.0 mg 57.8 Carbohydrate 100.0 mg 23.1 Stearic acid 20.0 mg 4.6 Zinc stearate 6 , 0.4 mg 1.4 Blue pigment &quot; FD &amp; C Blue # 2 Lake &quot; 6.5 mg 1,! 432.5 mg

30 A 1 (-) - norephedrine, compressible sugar, carbomer,. stearic acid and the blue pigment &quot; FD &amp; C Blue # 2 Lake &quot; are compacted into rolls and divided into portions of suitable size, the zinc stearate being then dry mixed. The mixture is compressed in a tablet press. The tablets are thus obtained.

Example VII

An extended-acting dosage composition according to the present invention is constituted by the following components:

Mod. 71-10000 ex. - 89/07 63474 Case N544

Ingredient

Per Unit Dose Percent by Weight 1 (-) - 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 lactose

(-) - norephedrine moistened with hydroxypropylmethylcellulose, and then dried and put to the appropriate size. The remaining ingredients are sequentially mixed dry, followed by compression in a tablet press. Example VIII granulated medium to a long-acting dosage composition, according to the present invention, is constituted by the following components: Ingredient Per Serving% Percentage by Weight 1 (-) - norephedrine 40 mg 7.3 25 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 30 FD & C Blue # 2 &quot; 8 mg 1.4 553 mg

All ingredients are put to the appropriate size, dry blended sequentially and compressed in a tablet press to obtain the tablets.

Example IX 5

An immediate release liquid dosage composition according to the present invention comprises the following components

Ingredient Per liter Percentage < weight / volume &gt; 10

Mod. 71 -10000 ex. Purified water 1 (~) Norephedrine Citric acid, anhydrous Sodium benzoate Sodium chloride Sodium saccharin Sucrose Sorbitol solution Glycerin Mixed fruit aroma (natural and artificial) Yellow &quot; FD &amp; C Yellow No. 6 &quot; Purified water as much (qb) to 1 liter 400.0 9 - 2.0 9 0.2 1.2 9 0.12 1.2 9 0.12 5.3 9 0.53 2.5 9 0.25 120.0 '3 12.0 450.0 9 45.0 60.0 9 6.0 8.0' 3 0.8. 0.1 9 0.01 The purified water is heated by dissolving 1 (-) - norephedrine, anhydrous citric acid, sodium benzoate, sodium chloride, sodium saccharin, sucrose, and pigment yellow &quot; FD &amp; C Yellow nS 6 &quot;. The solution is cooled and the sorbitol solution, glycerin, mixed fruit aroma and a sufficient amount of purified water are added to make up to one liter of the immediate release liquid composition.

One teaspoon full (5 cc) contains 10 mg of 1 (-) norephedrine. - 23 - 30 10 15

Mod. 71-10000 ex. - 89/07 20 25 30 63474 Case N544

Example X An immediate release dosage composition for use in accordance with the present invention is constituted by the following components

Ingredients

Per tablet

Percent by weight (Racemic mixture of d (+) - norephedrine and (~) norephedrine) HCl 37.5 mg 9.9 Microcrystalline cellulose 100.0 mg 26.5 Compressible sugar 200.0 mg 53.0 Glycolate of sodium starch 10.0 mg 2.0 Stearic Acid 15.0 mg 4.0 Talc 15.0 mg 4.07 mg

All ingredients are put to the appropriate size, dry blended and compressed in a tablet press to give the tablets. Example XI A sustained release composition for dosage use according to the present invention consists of the following ingredients: Ingredient Guaifenesin

Per tablet

Percent Weight 400 mg 51.3 (cont.) - 24 - 35 63474 Case N544

(cont'd) 1 (Racemic Mixture of d (+> g) -Norephedrine (-) - Norefibridine HCL 75 mg 9.6 Carbohydrate 117 mg 13.0 Blue Pigment &quot; FD &amp; C Blue # 1 A1uminum Lake) 3 mg 0.4 Compressible sugar 139 mg 17.8 Stearic acid 40 mg 5.1 Zinc stearate 6 mg 0.8 780 mg 15

Mod. 71-10000 ex. Guaifenesin, a (racemic mixture of d (+) - norephedrine and 1 (™ &gt; -norephedrine) HCL, the carbomer, pigment and stearic acid are compacted by rollers and placed in the appropriate size The compressible sugar and zinc stearate are added, the blend being then compressed into a tablet press to obtain the tablets. Example XII To a thirty-five year old woman afflicted with sinusitis characterized by congestion of the upper respiratory tract and retention of thick mucus and other thick respiratory secretions, a tablet formulated according to Example X is administered four times a day. Administration of the above tablet results in decongestion and drainage of the mucus and respiratory secretions. a twenty-five-year-old man afflicted with sinusitis characterized by the retention of thick mucus and other thick respiratory secretions formulated according to Example X, four times a day. Administration of the abovementioned tablet 25 - 35 10 15 15

Mod. 71 -10000 ex. - 89/07 20

30 63474 Case N544

results in the drainage of mucus and other respiratory secretions. Example XIV A 10-year-old child suffering from otitis media characterized by congestion of the Eustachian tube and retention of thick respiratory secretions, especially thick mucus, is given a capsule formulated according to Example III, four times a day. Administration of the above capsule results in the drainage of mucus and other respiratory secretions. Example XV To a forty-three year old man afflicted with sinusitis characterized by the retention of thick respiratory secretions, especially thick mucus, a tablet formulated according to Example V is administered three times a day. Administration of the above tablet results in the drainage of mucus and other respiratory secretions. Example XVI To a man of thirty-seven years of age, suffering from persistent cough, post nasal discharge and retention in thick nasal and sinus mucus and other respiratory secretions, a tablet formulated according to Example VI is administered orally , twice a day. Administration of the above tablet results in the suppression of persistent cough and drainage of the mucus and other retained respiratory secretions.

Example XVII To a man of forty-four years of age suffering from nasal and sinus congestion and retention of thick mucus and other respiratory secretions, a 75 mg tablet of a composition containing 1 (-) - norephedrine and guaifenesin "two - 26 - 35

Claims (3)

63474 Case N544 times per day Administration of the above tablet results in nasal and sinus decongestion and drainage of mucus and other retained respiratory secretions. Example XVIII To a three-year-old child suffering from otitis media characterized by congestion of the Eustachian tube and retention of thick respiratory secretions, especially thick mucus, half a teaspoon of the formulation of Example IX is administered four times daily Administration of the aforesaid liquid results in the drainage of mucus and other respiratory secretions. = CLAIMS = Mod. 71 -10000 ex. - 89/07 11. A process for the preparation of an oral composition for combating sinusitis or otitis media characterized in that an effective and safe amount of 1 (-) norephedrine and a pharmaceutically acceptable excipient is mixed. A process according to claim 1, characterized in that 1 (-) - norepinephrine is present in a level between about 27 and 30 ° C. A composition according to claim 2 wherein the oral composition further comprises a compound selected from the group consisting of non-steroidal drugs, non-narcotic analgesics, anti-inflammatory drugs, non-steroidal drugs, non-narcotic analgesics, spectromatants, antihistamines, anti-cough, anti-bacteria and corresponding combinations. A method according to claim 3, wherein the non-steroidal, analgesic, non-narcotic anti-inflammatory drug is selective from the group consisting of aspirin, ibuprofen and naproxen. - 27 - 35 * * 10 15 Mod. 71-10000 ex. - 89/07 J 25 30 5. A method according to claim 3, wherein the non-steroidal non-narcotic analgesic drug is acetaminophen. 6. A process according to claim 3, wherein the anti-bacterial medicament is selected from the group consisting of cefaclor, amoxicillin, amoxicillin and clavulanic acid, cefixime, ciprofloxacin and trimethoprim / sulfametaxazole. 7. A process according to claim 3, wherein the antitoside drug is selected from the group consisting of dextromethorphan and codeine. 8. A process according to claim 3, wherein the antihistamine drug is selected from the group consisting of chlorpheniramine, terfenadine, defenhydramine, fenindamine, pyrilamine, astemizole, loratadine, acrivastine, cetirizine and azalastine. 9. A medicament according to claim 3, wherein the expectorant medicament is selected from the group consisting of guaifenesin, carboxymethylcysteine, iodinated glycerol, acetylcysteine, ambroxol and sobrerol. 10. A composition according to claim 2 for the preparation of an immediate form of dose release characterized in that the pharmaceutically acceptable excipient comprises: (a) a filler at a level of from 207 to 70 %? and (b) a disintegrant at a level between 0.1-7 and 37; and &lt; c) a lubricant at a level of from 0.5 to 7.7. A process according to claim 10, wherein the pharmaceutically acceptable excipient further comprises: (a) a binder at a level of from 1.0 to 10 7 .; and (b) pharmaceutical dyes or pigments at levels between 0.05% and 2%. A process according to claim 2 for the preparation of a controlled dose release form characterized in that the pharmaceutically acceptable excipient comprises; &lt; a &gt; a polymer material at a level comprised at 10 7 and 40 7? and &lt; b &gt; a lubricant at a level of from 0.1 to 7.7; and (c) a filler at a level of from 20.7 to 70% wt. &lt; d &gt; dyes or pharmaceutical pigments at a level of from 0.05 to 2%. I declare that the words &quot; specify only &quot; Lisbon, 21.MAI.199i by NORWICH EATON PHARMACEUTICALS, INC. / OF OFFICIAL AGENT «ASCO MARQUES L« f € Affiliate 0 | icl ·! d »Industrial Property C * ftòrl · · Conceiç · ·. 3, i.mwi mm 29 -