EP0530311A1 - Utilisation de phenylpropanolamine comme secretagogue muqueux des voies respiratoires superieures - Google Patents

Utilisation de phenylpropanolamine comme secretagogue muqueux des voies respiratoires superieures

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Publication number
EP0530311A1
EP0530311A1 EP91911164A EP91911164A EP0530311A1 EP 0530311 A1 EP0530311 A1 EP 0530311A1 EP 91911164 A EP91911164 A EP 91911164A EP 91911164 A EP91911164 A EP 91911164A EP 0530311 A1 EP0530311 A1 EP 0530311A1
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EP
European Patent Office
Prior art keywords
norephedrine
level
oral composition
respiratory
safe
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP91911164A
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German (de)
English (en)
Inventor
Roger John Phipps
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Warner Chilcott Pharmaceuticals Inc
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Norwich Eaton Pharmaceuticals Inc
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Publication of EP0530311A1 publication Critical patent/EP0530311A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants

Definitions

  • 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):
  • 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, PhenylDropanolamine - A Review, p.28 (1980)). These are 1(-)- norephedrine and d(+)-norpseudoephedrine.
  • the d(+)-norpseudo- ephedrine iso er is a naturally occurring substance found primarily in the shrub Catha edul is 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 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.
  • 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.
  • 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.
  • transudation is the loss of fluid from the nasal blood vessels into the nasal tissues
  • active secretion from cells in the respiratory mucosa and the nasal glands that secrete mucus.
  • 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.
  • 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.
  • 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 H PPA”) to induce mucous secretion in the upper airways of persons afflicted with sinusitis or otitis media characterized by retention of thickened respiratory secretions.
  • H PPA phenylpropanolamine
  • 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.
  • 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.
  • 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 syste ⁇ rically 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. Head and Neck, p. 207 (1985) and Geldman, The Principles and Practice of Rhinoloqy. 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 eustach.ian 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.
  • nasal congestion refers to an increase in resistance to nasal air flow caused by increased blood volume in the nasal tissues.
  • 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.
  • the preferred techniques for measuring mucous viscoelasticity are capillary viscometry and magnetic microrheometry.
  • 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 (CD.), Barnett (B.), Dulfano (M.J.), "A Method for Determining the Viscoelastic Properties of Biological Fluids", Biorheologv. pp. 55-67 (1970); Lutz (R.J.), Litt (M.), Chakrin (L.), "Physical-Chemical Factors in Mucus Rheology", Rheoloov of Biological Systems. H. L. Gabelnick and M. Litt (eds.), Thomas, Springfield, pp. 119-157 (1973), which are incorporated herein by reference.
  • the dosage regimen consists of administration of PPA one to four times per day.
  • 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.
  • 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.
  • 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, iroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, and pharmaceutically acceptable salts thereof.
  • Antibacterials among those useful include, but are not limited to, the following: cefaclor, cefadroxil, cefuroxime axetil, cephalexin, cephradine, cefixi e, cefcanel daloxate, cefteram pivoxil, cefpodoxime, a picillin, 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, sul
  • 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, bromphenira ine, dexchlorpheniramine, dexbrompheniramine, tripolidine, diphenhydramine, doxylamine, tripelenna ine, 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.
  • expectorant does not refer to l(-)-nor- ephedrine, 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 .
  • compositions of this invention are preferably provided in unit dosage form.
  • a "unit dosage form” is a composition of this invention containing an amount of
  • racemic mixtures of dl-norephedrine or dl-norpseudoephedrine may be separated from each other by fractional crystallization, taking advantage of their different solubilities.
  • melting points mp were reported for the purified racemates (Hoover, F. W., & Hass, H. B., Synthesis of 2-amino-l-phenyl-l-propanol and Its Methylated Derivatives, jh. Pro. Chem.. Vol. 12, pp. 506-509 (1947)).
  • 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. Pro. Chem.. Vol. 25, pp. 1929-1937 (I960)). These salts are diastereoisomers that can be separated by fractional crystal- lization, 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 unit dosage from will typically contain from 10 mg to 100 mg of 1 (-)-norephedrine.
  • the unit dosage form will be from 10 mg to 50 mg of 1(-)-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 1(-)- norephedrine is sufficient to provide a practical quantity of material for administration per unit dose of the l(-)-norephed- rine.
  • the 1 (-)-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.
  • the excipient base or polymer excipient base comprises at least 50% by weight of the dose form.
  • a preferred immediate release liquid comprises:
  • 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
  • a preservative at a level from about 0.004% to 1%
  • a sweetening agent at a level from about 0.25% to 20%
  • a flavoring agent at a level from about 0.01% to 2%
  • pharmaceutical grade dyes or pigments may be used at levels from about 0.05% - 2.0%
  • 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 Publish- ing 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, hydroxypropyl ethylcellulose, carbomer, povidone, acacia, guar gum, xanthine gum and tragacanth.
  • methylcellulose particularly preferred are methylcellulose, xanthine gum, guar gum, povidone and sodium carboxymethylcellulose.
  • a preferred immediate release capsule comprises:
  • 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
  • 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%.
  • 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, 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
  • 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.
  • cellulose ethers such as methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and sodium carboxymethylcellulose
  • polyvinylpyrrolidone polyvinylpyrrolidone
  • mixtures of natural hydrophilic gums such as guar gum, gum Karaya, gum tragacanth, and xanthine gum
  • synthetic hydrophilic polymers such as carbomer
  • hydroxy- propylmethylcellulose 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.
  • An immediate release tablet composition comprising the following components:
  • the tablet is made by wet granulating the 1 (-)-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:
  • the tablet is made by wet granulating the 1 (-)-norephedrine hydrochloride, ibuprofen, chlorpheniramine maleate, dextromethor ⁇ phan hydrobromide with a gelatin solution. The granulation 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: Ingredient Per Capsule Percent by Weight l(-)-norephedrine 25 mg 19.5
  • An immediate release tablet composition is made comprising the following components:
  • 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:
  • a long acting dosage composition comprising the following components:
  • a long acting dosage composition comprising the following components:
  • a long acting dosage composition is made comprising the following components:
  • EXAMPLE IX An immediate release liquid dosage composition, according to the present invention, is made comprising the following components: Ingredient Per Liter Percentfwt./volume
  • Citric Acid anhydrous 1.2 g 0.12
  • Sorbitol Solution 450.0 g 45.0
  • 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.
  • An immediate release dosage composition for use according to the present invention, is made comprising the following components:
  • a long acting release dosage composition for use according to the present invention, is made comprising the following
  • 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.
  • 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 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 1(-)-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.

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Abstract

L'invention se rapporte à un nouveau procédé d'utilisation de la U phénylpropanolamine pour induire des sécrétions muqueuses dans les voies respiratoires supérieures de personnes souffrant d'infections telles que la sinusite ou l'otite, lesquelles se caractérisent par la rétention de sécrétions respiratoires épaissies. Ces procédés consistent à administrer à un patient souffrant d'une telle infection une quantité sûre et efficace de U phénylpropanolamine. L'invention se rapporte également à certaines nouvelles compositions à administrer par voie buccale, qui se composent essentiellement de l(-)-noréphédrine et d'une base excipient pharmaceutiquement acceptable.
EP91911164A 1990-05-21 1991-05-17 Utilisation de phenylpropanolamine comme secretagogue muqueux des voies respiratoires superieures Withdrawn EP0530311A1 (fr)

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EP (1) EP0530311A1 (fr)
JP (1) JPH05509300A (fr)
AU (2) AU7992091A (fr)
CA (1) CA2083403A1 (fr)
IE (1) IE911711A1 (fr)
IL (1) IL98179A0 (fr)
MX (1) MX173793B (fr)
PT (1) PT97730A (fr)
WO (1) WO1991017746A1 (fr)
ZA (1) ZA913831B (fr)

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JPH069382A (ja) * 1992-04-17 1994-01-18 Takeda Chem Ind Ltd 安定化された固型製剤およびその製造方法
ES2065846B1 (es) * 1993-04-20 1995-10-01 Cusi Lab Formulacion farmaceutica a base de un agente antiinflamatorio esteroidico o no esteroidico y un antibiotico pertenciente al grupo de los inhibidores de la adn girasa para su utilizacion topica oftalmica.
AU676315B2 (en) * 1993-06-30 1997-03-06 Takeda Chemical Industries Ltd. Stabilized solid pharmaceutical preparation and method of producing the same
ZA963590B (en) * 1995-05-10 1996-11-19 Adcock Ingram Ltd Pharmaceutical composition
US6469009B1 (en) * 1996-04-08 2002-10-22 Ucb, S.A. Pharmaceutical compositions for the treatment of rhinitis
CA2305294A1 (fr) * 1998-03-23 1999-09-30 Thomas Yorio (-)-phenylpropanolamine en tant que medicament sympathomimetique
WO2005123052A1 (fr) * 2004-06-18 2005-12-29 Jiangsu Hengrui Medicine Co., Ltd. Composition medicamenteuse contenant de l'ambroxol et de l'erdosteine ou de l'acetylcysteine
WO2006093784A2 (fr) * 2005-02-25 2006-09-08 Mutual Pharmaceutical Company, Inc. Antibiotiques, ainsi que combinaisons d'antibiotiques et de formulations d'agents de soulagement symptomatique
BRPI0720337A2 (pt) 2007-01-12 2015-09-29 Angus Chemical "composição biocida, método para inibir o crescimento de microorganismo em um sistema base aquosa, composição na qual o crescimento microbiano está inibido e composto"
MX2010012447A (es) 2008-05-15 2010-12-20 Angus Chemical Control microbiano y corrosion mejorados en composiciones hidrocarbonaceas.
JP5670882B2 (ja) 2008-05-15 2015-02-18 アンガス ケミカル カンパニー アミノアルコールおよび水系システム用の殺生剤組成物
US11278506B2 (en) 2015-10-09 2022-03-22 Rb Health (Us) Llc Pharmaceutical formulation
CN111346100A (zh) * 2020-04-16 2020-06-30 四川大学华西医院 阿司匹林或其衍生物在制备治疗气道粘液高分泌的药物中的用途

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US4818541A (en) * 1987-08-19 1989-04-04 Schering Corporation Transdermal delivery of enantiomers of phenylpropanolamine

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ZA913831B (en) 1992-02-26
IL98179A0 (en) 1992-06-21
JPH05509300A (ja) 1993-12-22
PT97730A (pt) 1992-02-28
WO1991017746A1 (fr) 1991-11-28
MX173793B (es) 1994-03-25
AU2050895A (en) 1995-08-03
IE911711A1 (en) 1991-12-04
CA2083403A1 (fr) 1991-11-22
AU7992091A (en) 1991-12-10

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