WO2005084330A2 - Compositions et methodes de traitement de la congestion nasale - Google Patents

Compositions et methodes de traitement de la congestion nasale Download PDF

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Publication number
WO2005084330A2
WO2005084330A2 PCT/US2005/006726 US2005006726W WO2005084330A2 WO 2005084330 A2 WO2005084330 A2 WO 2005084330A2 US 2005006726 W US2005006726 W US 2005006726W WO 2005084330 A2 WO2005084330 A2 WO 2005084330A2
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WO
WIPO (PCT)
Prior art keywords
nasal
nasal congestion
threo
amount
congestion
Prior art date
Application number
PCT/US2005/006726
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English (en)
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WO2005084330A3 (fr
Inventor
Stephen J. Peroutka
Original Assignee
Synergia Pharma, Inc.
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Publication date
Application filed by Synergia Pharma, Inc. filed Critical Synergia Pharma, Inc.
Publication of WO2005084330A2 publication Critical patent/WO2005084330A2/fr
Publication of WO2005084330A3 publication Critical patent/WO2005084330A3/fr

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Classifications

    • 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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic 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
    • A61K31/33—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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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

Definitions

  • Fig. 1 shows the ability of L-DOPS to antagonize the nasal congestion effects of compound 48/80.
  • the arrow indicates when the active agent was administered.
  • the present invention relates to articles of manufacture, compositions, and methods for treating nasal congestion, and associated disorders and conditions, in a subject in need thereof.
  • the methods involve administering effective amounts of a norepinephrine precursor.
  • the norepinephrine precursor can be administered with other effective compounds, such as histamine H1 receptor antagonists and leukotriene antagonists, which in combination can be utilized to treat nasal congestion.
  • a norepinephrine precursor is administered in amounts that are effective to treat nasal congestion.
  • treating is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving, etc., nasal congestion.
  • nasal congestion refers to any condition in which the nose, nasal sinuses, and/or associated nasal passages, become obstructed or blocked. Treating with a norepinephrine precursor can reduce the frequency, severity, intensity, and/or duration of any of the symptoms associated with nasal congestion.
  • the nasal sinuses are small mucus-lined pockets within the facial bones surrounding the nose. The human body produces approximately one liter per day of mucous in the nasal sinuses. The mucous must then pass through small (2 mm) openings, called the ostia, for drainage through the nose and throat. When the sinuses are healthy, the mucous drains easily from them into the nose, and air also passes freely, both in and out through the nose.
  • Nasal congestion occurs when the ostia are constricted or blocked. Most commonly, the blockade occurs when the blood vessels within the membranes lining the nasal passages becoming dilated and/or inflamed. For example, viral infection of mucous membranes in the nose causes blood vessels to dilate, causing local swelling and ostia blockage. Mucous is thereby trapped in the sinuses, causing the subjective sensation of nasal congestion. While not wishing to be bound to any theory or mechanism of action, a norepinephrine precursor can be used to treat nasal congestion by stimulating, producing, increasing, increasing, augmenting, enhancing, etc., the contraction of nasal blood vessels, thereby relieving nasal congestion and its associated symptoms.
  • a reduction in the diameter of the nasal blood vessels, and/or the volume of nasal blood vessels, and/or the nasal blood flow, can be effective for treating nasal congestion.
  • Any quantity or amount of reduction that is adequate to relieve the congestion can be included in the present invention.
  • the present invention relates to the use of norepinephrine precursors, irrespective of the mechanism through which they act.
  • Compounds of the present invention can also be used to increase nasal patency as measured by acoustic rhinometry, a noninvasive technique to evaluate changes in the geometry of the nasal cavity. See, e.g., Koss et al., J. Appl. Physiol., 92:617-621 , 2002.
  • Nasal patency refers to the degree of openness of the nasal cavity.
  • a compound of the present invention was effective in increasing nasal patency, thereby treating nasal congestion.
  • Any norepinephrine precursor that is effective in treating nasal congestion can be used.
  • a norepinephrine precursor comprises any compound that is converted into norepinephrine.
  • norepinephrine such as threo-3-(3, 4-dihydroxyphenyl)serine (threo-DOPS)
  • dopamine beta-hydroxylase a substrate of the enzyme dopamine beta-hydroxylase that can be converted to norepinephrine, such as dopamine.
  • the norepinephrine precursor can be used for the synthesis of norepinephrine, and therefore can increase its levels in the appropriate tissues.
  • the present invention also relates to methods of treating nasal congestion in a subject in need thereof, comprising, administering to the subject an amount of threo-3- (3,4-dihydroxyphenyl) serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof, which is effective to treat nasal congestion.
  • the methods of the present invention can be utilized to treat nasal congestion, regardless of its cause.
  • nasal congestion is the most common and bothersome symptom of rhinitis (i.e., an inflammatory response in the nose).
  • rhinitis i.e., an inflammatory response in the nose.
  • Non-allergic types of rhinitis include, but are not limited to, vasomotor rhinitis, irritative rhinitis, and drug-induced rhinitis.
  • compositions of the present invention can be used for the symptomatic relief of nasal inflammation or congestion due to infection of the nasal mucosa, sinus inflammation or congestion and inflammation or congestion associated with the Eustachian tube and other associated nasal and passages and sinus cavities, sinusitis, etc.
  • Nasal congestion can also be caused by (or associated with) infection (e.g.
  • Drug-induced nasal gestation includes "rebound congestion" which is produced by the excessive use of nasal sprays or nose drops administered in response to nasal obstruction.
  • certain medications produce nasal congestion as an undesirable side-effect, such as prazosin, guanethidine, reserpine, cocaine, etc.
  • Nasal congestion can be associated with other conditions and disorders, including, but not limited to, sinus pain, impaired taste and/or smell, difficulty breathing, disturbed sleeping, impaired appetite, head pain, etc.
  • the compositions and methods of the present invention can be utilized to treat one or more of the aforementioned conditions, as well any other that is associated with nasal congestion or nasal membrane dysfunction.
  • a norepinephrine precursor may be used as adjunct therapy with analgesics, antibiotics, antitussives, antihistamines or expectorants in treatment of respiratory tract disease.
  • the norepinephrine precursor may be used alone or in combination with a histamine H1 receptor antagonist and/or a leukotriene antagonist.
  • H1 receptor antagonists include, but are not limited to, mepyramine, chlorpheniramine, diphenhydramine, terfenadine, astemizole, loratadine, cetirizine.
  • suitable leukotriene antagonists include, but are not limited to, montelukast
  • the specific dose level and frequency of dosage may vary, depending upon a variety of factors, including the activity of the specific active agent, its metabolic stability and length of action, rate of excretion, mode and time of administration, the age, body weight, health condition, gender, diet, etc., of the subject, and the severity, intensity, and frequency of the symptoms associated with nasal congestion.
  • a precursor in accordance with the present invention can be immediately effective in achieving therapeutic efficacy, or it can reach its maximal effect after multiple or regularly administered doses, e.g., one or more doses a day for a week, two weeks, a month, etc.
  • Threo-3-(3,4-dihydroxyphenyl)serine is a synthetic amino acid precursor of NE (Freeman R., Clin. Neuropharm., 14, 296-304, 1991 ).
  • DOPS is directly converted to NE via L-aromatic amino acid decarboxylase (AADC), also known as dopa decarboxylase (DDC).
  • AADC L-aromatic amino acid decarboxylase
  • DDC dopa decarboxylase
  • DOPS has been used to treat motor or speech disturbances (e.g., U.S. Pat. No.
  • Any effective amount of threo-3-(3,4-dihydroxyphenyl)serine can used, e.g., from about 10 mg to about 1200 mg per day or per dosage unit, about 50 mg to about 600 mg per day or per dosage unit, about 100 mg to about 400 mg per day or per dosage unit, about 300 mg per day or per dosage unit, etc.
  • Effective amounts can be determined routinely, and may vary depending upon the age, health, gender, and weight of a patient, as well as the severity, frequency, and duration of the nasal congestion. Amounts can be administered in a multiple doses over the course of the day, e.g., in order to achieve a therapeutic effect.
  • Threo-3-(3,4-dihydroxyphenyl) serine can be prepared according to any suitable method. These processes include those described in, e.g., U.S. Pat. Nos. 4,480,109,
  • L-threo-DOPS L-threo-DOPS.
  • Pharmaceutically-acceptable salts of threo-3-(3,4-dihydroxyphenyl)serine can also be used, including addition salts, e.g., inorganic acids, such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids, such as fumaric acid, citric acid, tartaric acid, and succinic acid. Any pharmacologically active derivative of threo-3-(3,4-dihydroxyphenyl)serine can be used.
  • N-methyl-3-(3,4-dihydroxyphenyl)serine alkyl esters such as N-methyl-D,L-threo-3-(3,4-dihydroxyphenyl)serine and N-methyl-L-threo-3-(3,4 dihydroxyphenyl)serine
  • lower alkyl esters methyl esters, ethyl esters, n-propyl esters, isopropyl esters, etc., as described in U.S. Pat. No. 5,288,898.
  • Precursors can be further combined with any other suitable additive or pharmaceutically acceptable carrier.
  • Such additives include any of the substances already mentioned, as well as any of those used conventionally, such as those described in Remington: The Science and Practice of Pharmacy (Gennaro and Gennaro, eds, 20th edition, Lippincott Williams & Wilkins, 2000); Theory and Practice of Industrial Pharmacy (Lachman et al., eds., 3rd edition, Lippincott Williams & Wilkins, 1986); Encyclopedia of Pharmaceutical Technology (Swarbrick and Boylan, eds., 2nd edition, Marcel Dekker, 2002). These are generally referred to herein as "pharmaceutically acceptable carriers" to indicate they are combined with the active drug and can be administered safely to a subject for therapeutic purposes.
  • the present invention also relates to combinations of at least two active agents, comprising a norepinephrine precursor, and, but not limited to, histamine H1 receptor antagonists, leukotriene antagonists, acetaminophen, sympathomimetics, antihistamines, alphal- and alpha2-adrenergic agonists, NSAIDS, non-NASAIDS, etc.
  • Compositions can also comprise additional agents, such as salicylic acids (e.g., aspirin, salicylate, and diflunisal), acetic acids (e.g., diclofenac, indomethacin, sulindac, and tolmetin), propionic acids (e.g., fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, naproxen, and pirprofen), anthranilic acids (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, and tolfenamic acid), pyrazolones (e.g., phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, and dipyrone), oxicams (e.g., piroxicam), etc.
  • salicylic acids e.g., aspirin, salicylate, and diflunisal
  • These compounds can be combined in effective amounts, e.g., effective to treat pain and/or fever associated with nasal congestion and/or diseases/conditions associated with nasal congestion (e.g., influenza, colds, allergy, viral diseases, bacterial diseases, etc). These combinations can comprise synergistic amounts of these agents.
  • the combinations can be in any effective form, e.g., as compositions where the two agents are present in the same dosage unit, as a "multi-pill" unit which contains separate dosage units of the norepinephrine precursor and the second active agent, etc.
  • the active agents can be in any suitable form, without limitation.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
  • Compositions comprising precursors can also be formulated for controlled release, where release of the active ingredient is regulated or modulated to achieve a desired rate of delivery into the systemic circulation.
  • a controlled release formulation can be pulsed, delayed, extended, slow, steady, immediate, rapid, fast, etc. It can comprise one or more release formulations, e.g. extended- and immediate- release components.
  • compositions can be delivered to a subject in need of treatment through any suitable delivery means.
  • a nasal delivery device For example, for local delivery to the nasal passages, devices that introduce compositions into the naval cavity can be utilized, i.e., a nasal delivery device.
  • Nasal solutions can be aqueous solutions for administration by spray or drops. The dose can be metered by the spray pump or could have been pre-metered during manufacture.
  • a nasal spray unit can be designed for unit dosing or can discharge up to several hundred metered sprays of formulation containing the drug substance. Dry formulations can also be used.
  • Nasal delivery devices include, e.g., devices described in U.S. Pat. Nos. 6,644,305, 6,065,471 , 5,437,267, 5,983,893, etc.
  • Any suitable dosing interval can be used in accordance with the present invention.
  • Extended delivery systems can be utilized to achieve a dosing internal of once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, etc.
  • the dosage form/delivery system can be a tablet or a capsule suited for extended release, but a sustained release liquid or suspension can also be used.
  • a controlled release pharmaceutical formulation can be produced which maintains the release of, and or peak blood plasma levels of, threo-3-(3, 4-dihydroxyphenyl) serine, derivative thereof, or salt thereof, over a period of at least 6 hours, 12 hours, 18 hours, 24 hours, etc.
  • Norepinephrine precursors in accordance with the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasal, local, non-oral, such as aerosal, spray, inhalation, subcutaneous, intravenous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. It can be administered alone, or in combination with any ingredient(s), active or inactive.
  • Ada 920, 301-305, 1987 was administered as an intranasal mist to a single naris, to elicit nasal congestion in six conscious beagle dogs.
  • Compound 48/80 caused a decrease of nasal cavity volume (to about 50% of control). Maximal responses were seen at 90-120 min after 48/80 administration and were of similar magnitude when trials were repeated.
  • the oral administration of the adrenergic agonist, d- pseudoephedrine (3.0 mg/kg) significantly antagonized all of the nasal effects of compound 48/80.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des compositions et des méthodes de traitement de la congestion nasale chez un patient. Lesdites méthodes consistent, par exemple, à administrer une certaine quantité d'un précurseur de norépinéphrine, ladite quantité étant efficace pour traiter la congestion nasale. L'invention concerne également des compositions et des méthodes de fabrication de celles-ci, utilisées dans le traitement de la congestion nasale seules ou en combinaison avec un antagoniste du récepteur H1 de l'histamine et/ou un antagoniste de leucotriène. Le précurseur de la norépinéphrine utilisé est la thréo-3-(3,4-dihydroxyphényl) sérine, un dérivé de celle-ci, ou un sel acceptable d'un point de vue pharmaceutique de celle-ci.
PCT/US2005/006726 2004-03-02 2005-03-02 Compositions et methodes de traitement de la congestion nasale WO2005084330A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US54887604P 2004-03-02 2004-03-02
US60/548,876 2004-03-02

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WO2005084330A2 true WO2005084330A2 (fr) 2005-09-15
WO2005084330A3 WO2005084330A3 (fr) 2006-01-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015006315A1 (fr) 2013-07-08 2015-01-15 Auspex Pharmaceuticals, Inc. Composés neurotransmetteurs hydroxyphényles

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656669A (en) * 1994-07-05 1997-08-12 Sumitomo Pharmaceuticals Co., Ltd. Restorative neuropharmacological agent for motor and speech disturbance
US20010053787A1 (en) * 1992-09-03 2001-12-20 Sepracor Inc. Compositions for treating alergic and other disorders using norastemizole in combination with other active ingredients
US6384038B1 (en) * 1998-04-14 2002-05-07 Sepracor Inc. Methods and compositions using cetirizine in combination with leukotriene inhibitors or decongestants
US20040191176A1 (en) * 2003-03-28 2004-09-30 Kaplan Leonard W Formulations for treatment of pulmonary disorders
US20040248924A1 (en) * 2001-09-18 2004-12-09 Moesgaard Hanne Anette Compositions for treatment of common cold

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010053787A1 (en) * 1992-09-03 2001-12-20 Sepracor Inc. Compositions for treating alergic and other disorders using norastemizole in combination with other active ingredients
US5656669A (en) * 1994-07-05 1997-08-12 Sumitomo Pharmaceuticals Co., Ltd. Restorative neuropharmacological agent for motor and speech disturbance
US6384038B1 (en) * 1998-04-14 2002-05-07 Sepracor Inc. Methods and compositions using cetirizine in combination with leukotriene inhibitors or decongestants
US20040248924A1 (en) * 2001-09-18 2004-12-09 Moesgaard Hanne Anette Compositions for treatment of common cold
US20040191176A1 (en) * 2003-03-28 2004-09-30 Kaplan Leonard W Formulations for treatment of pulmonary disorders

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015006315A1 (fr) 2013-07-08 2015-01-15 Auspex Pharmaceuticals, Inc. Composés neurotransmetteurs hydroxyphényles
EP3611159A1 (fr) 2013-07-08 2020-02-19 Auspex Pharmaceuticals, Inc. Composés neurotransmetteurs de dihydroxyphényle, compositions et procédés

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