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WO1997001340A1 - Combinaison d'antihistamines nasales topiques et de stabilisateurs de mastocytes topiques par voie nasale - Google Patents

Combinaison d'antihistamines nasales topiques et de stabilisateurs de mastocytes topiques par voie nasale Download PDF

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Publication number
WO1997001340A1
WO1997001340A1 PCT/US1996/010810 US9610810W WO9701340A1 WO 1997001340 A1 WO1997001340 A1 WO 1997001340A1 US 9610810 W US9610810 W US 9610810W WO 9701340 A1 WO9701340 A1 WO 9701340A1
Authority
WO
WIPO (PCT)
Prior art keywords
nasal
mast cell
topical
lodoxamide
nedocromil
Prior art date
Application number
PCT/US1996/010810
Other languages
English (en)
Inventor
Eileen Helzner
Original Assignee
Mcneil-Ppc, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Mcneil-Ppc, Inc. filed Critical Mcneil-Ppc, Inc.
Priority to AU61811/96A priority Critical patent/AU6181196A/en
Publication of WO1997001340A1 publication Critical patent/WO1997001340A1/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
    • A61K31/33—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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose

Definitions

  • the present invention relates to prevention and treatment of the symptoms of seasonal and perennial allergic rhinitis. More particularly, the present invention relates to the prevention and treatment of the symptoms of seasonal and perennial allergic rhinitis by the application of a combination of topical nasal antihistamines and topical nasal mast cell stabilizers.
  • rhinitis is most frequently caused by pollen, pollen fragments and mold spores.
  • the airborne pollens, pollen fragments and mold spores are deposited on the nasal mucosa.
  • rhinitis symptoms develop which include puffy, sore eyes, sneezing, nasal congestion, sinus headaches and fatigue.
  • perennial allergic rhinitis The chronic symptoms of perennial allergic rhinitis are most frequently caused by reaction to perennial allergens, such as, house dust mite, mold, cockroach, animal saliva, urine, and dander.
  • perennial allergens such as, house dust mite, mold, cockroach, animal saliva, urine, and dander.
  • the symptoms resemble those of seasonal allergic rhinitis but the duration is year round or episodic depending upon the source of the allergens.
  • Antihistamines are the primary medicaments employed to treat allergic rhinitis. Antihistamines are helpful to control sneezing, itching, and rhinorrhea as well as associated ocular symptoms but are ineffective in relieving nasal blockage. Antihistamines compete with histamine for binding to Hi receptors and thereby prevent the action of histamine which includes bronchospasm, edema, increased mucus secretion and itching.
  • the antihistamines primarily in use today are orally active and administered.
  • intranasally (topically) administered antihistamines including azelastine and levocabastine have also been shown to be useful antihistamines in the treatment of allergic rhinitis.
  • the intranasally administered antihistamines have a quick onset of action because they are delivered directly to the site of activity.
  • mast cell stabilizers employed to treat allergic rhinitis.
  • mast cells release mediators, which include, histamine, SRS-A, serotonin, adenosine, proteases, etc. which induce vasodilation, smooth muscle contraction, glandular secretion and stimulation of irritant nerve receptors among other symptoms.
  • Mast cell stabilizers inhibit the release of mediators from the mast cells and thereby block the symptoms of their release.
  • Suitable mast cell stabilizers known or in use today include cromolyn sodium, nedocromil and lodoxamide. Each of these mast cell stabilizers may be topically applied.
  • a nasal spray or nasal drops for the treatment of allergic rhinitis comprising:
  • a topical antihistamine to relieve histamine mediated symptoms
  • said topical nasal antihistamine is selected from the group consisting of azelastine and azatadine;
  • a topical mast cell stabilizer to inhibit mast cell mediator release
  • said topical nasal mast cell stabilizer is selected from the group consisting of cromolyn sodium, nedocromil and lodoxamide
  • the topical antihistamines herein are potent H 1 receptor antagonists which relieve the histamine mediated symptoms, i.e. sneezing, runny nose, itchy nose, etc.
  • the H 1 receptor antagonists block the receptor sites and thereby block the expression of the histamine effect.
  • azelastine or azatadine is employed. In the case of azelastine from about 0.05 to about 10 mg and preferably from about 0.5 to about 5 mg should be administered in this combination every 4 to 12 hours.
  • azatadine In the case of azatadine, from about 0.05 to about 10 mg and preferably from about 0.5 to about 5 mg should be administered in this combination every 4 to 12 hours.
  • azelastine should constitute of the nasal spray or nasal drops composition from about 0.2 to about 40 mg/ml and preferably from about 2 to about 20 mg/ml.
  • azatadine should constitute from about 0.2 to about 40 mg/ml and preferably from about 2 to about 20 mg/ml.
  • Azelastine as used herein includes azelastine and its pharmacutically acceptable salts.
  • Preferred are the acid addition salts, such as, the hydrohalo salts and salts with organic acids.
  • Preferred salts include hydrochloridic hydrobromidic, embonic acid, maleic acid, citric acid and tartaric acid salts.
  • Azelastine, 4-(p-chlorobenzyl)-2-[N-methyl-perhydroazepin-4-yl)-1-(2H)- phthalazinone, is a well known compound and may be prepared according to Belg. Pat. 778,269; Vogelsang et al., U.S. Pat. 3,813,384 and Scheffler et al., Arch. Pharm. 321 , 205 (1988).
  • Azatadine as used herein includes azatadine and its pharmaceutically acceptable salts.
  • Preferred salts of azatidine include its maleate, sulfate, succinate and acetate salts.
  • Aztadine, 4-aza-5-(N-methyl-4-piperidinylidene)- 10,11 -dinydro-5H-dibenzo[a,d]cycloheptene is a well known compound and may be prepared according to Belg. Pat. 647,043; U.S. Pat. 3,3577,986 and Villani et al., J. Med. Chem. 15, 750 (1972).
  • the topical nasal mast cell stabilizers herein function by preventing degranulation of mast cells in response to allergens. When allergens are present, they bind to the immunoglobulin on the surface of mast cells and trigger the breakdown, or degranulation, of the cell. Upon degranulation, mast cell components, including mediators for symptoms associated with allergic rhinitis, are released.
  • allergens When allergens are present, they bind to the immunoglobulin on the surface of mast cells and trigger the breakdown, or degranulation, of the cell. Upon degranulation, mast cell components, including mediators for symptoms associated with allergic rhinitis, are released.
  • cromolyn sodium, nedrocromil or lodoxamide is employed. In the case of cromolyn sodium, from about 0.5 to about 20 mg, and preferably from about 3 to about 15 mg should be administered in this combination every 4 to 12 hours.
  • nedocromil from about 0.1 to about 20 mg, and preferably from about 2 to about 8 mg should be administered every 4 to 12 hours.
  • lodoxamide from about 0.1 to about 30 mg, and preferably from about 2 to about 15 mg should be administered every 4 to 12 hours.
  • cromolyn sodium should constitute the nasal spray or nasal drops composition from about 2 to about 80 mg/ml and preferably from about 10 to about 60 mg/ml.
  • Nedocromil should constitute from about 1 to about 80 mg/ml and preferably from about 5 to about 30 mg/ml.
  • lodoxamide should constitute from about 1 to about 100 mg/ml and preferably from about 5 to about 60 mg/ml.
  • Cromolyn sodium is also known as disodium cromoglycate or simply
  • Cromolyn This compound has been marketed under the names Ital and Lomudal (Cox et al., Adv. in Drug Res., 5:115-195 (1970)). Cromolyn is the disodium salt of 1 ,3-bis-(2-carboxy-chromone-5'-yloxy)-2-hydroxypropane. Cromolyn is believed to interface with the mechanism leading to a transiently elevated [Ca 2+ ]j upon antigenic stimulation of the cell. Hence, it prevents histamine release.
  • Nedocromil as used herein inlcudes nedocromil and its pharmaceutically acceptable salts.
  • the preferred salts are the sodium and calcium salts.
  • Nedocromil, 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H- pyrano[3,2-g] guinoline-2,8-dicarboxylic acid inhibits the release and/or action of pharmacological mediators which result from the in vivo combination of certain types of antibodies and specific antigents, e.g. the combination of reaginic antibody with specific antigen (See Example 27 of Brit. Pat 1 ,292,601).
  • the preparation of nedocromil is described in Brit. Pat. 2022078, U.S. Pat. 4,474,787 and Cairns et al., J. Med. Chem. 28, 1832 (1985).
  • Lodoxamide as used herein includes lodoxamide and its pharmaceutically acceptable salts and esters.
  • the preferred salt of lodoxamide is its di-tris (hydroxymethyl) methyl ammonium (or bis THAM) salt and the preferred ester is the ethyl ester.
  • Lodoxamide is known to inhibit the release of mast cell mediators of inflammation.
  • the manufacture of lodoxamide, N,N'-(2-chloro-5-cyano-m-phenylene) dioxamic acid, is well known and taught in U.S. Pat. 3,962,308 and U.S. Pat. 3,993,679.
  • the nasal spray or nasal drop formulation herein can contain, in addition to the compounds discussed above antimicrobial agents, antioxidants, agents to increase viscosity, isotonic agents, buffers, solubilizing agents, surface active agents and the like.
  • Suitable antimicrobial agents include chlorobutanol, phenylmercuric nitrate, phenyl ethyl alcohol, thimerosal, the quatemary ammonium germicides, such as, benzalkonium chloride, benzethonium chloride or cetylpyridium chloride.
  • Suitable antioxidants include sodium sulfite, sodium ascorbate, oxime sulfate, etc.
  • the preferred isotonic agent is sodium chloride however, other isotonic agents such as dextrose, boric acid and sodium tartrate may be employed.
  • the object of the buffer is to adjust the pH to one compatible with nasal mucous membranes and to stabilize the active ingredient. Ideally the target pH should vary between about 4 and about 6.5. Suitable buffers included phthalate buffers, borate buffers, phosphate buffers, such as HP ⁇ 4 2 7H2P ⁇ 4"- acetate buffers, such as acetic acid/sodium acetate, a bicarbonate buffer such as CO2/HCO3, or a citrate buffer, such as citric acid/citrate, also it may be adjusted by simply adding an acid such as HCl to achieve the desired acidity.
  • Suitable agents to increase viscosity include polyvinyl alcohol, cellulose derivatives, polyvinylpyrollidone, polysorbates or glycerine.
  • Suitable surface active agents improve abso ⁇ tion by the nasal mucosa and include polyoxyl 40 stearate, polyoxyethylene 50 stearate, polysorbate 80 and octoxynol.
  • concentration of the additives will be in the range as follows:
  • the buffer should be added in sufficient amount to achieve the pH range stated above of about 4.0 to about 6.5.
  • Aerosol formulations and nose drops are prepared as per known techniques.
  • the water employed should be of an appropriate pharmacutical grade of purified water. These formulations should be administered by drop or spray every 4 to 12 hours to obtain the desired relief.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Otolaryngology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention se rapporte à un pulvérisateur nasal ou à des gouttes nasales pour le traitement de rhinites allergiques comprenant (a) une quantité efficace d'une antihistamine topique pour soulager les symptômes induits par l'histamine, où ladite antihistamine nasale topique est choisie parmi l'azélastine et l'azatadine; (b) une quantité efficace d'un stabilisateur de mastocytes topiques pour inhiber la libération du médiateur des mastocytes, où ledit stabilisateur de mastocytes topiques par voie nasale est choisi parmi le sodium de cromolyne, le nédocromil et le lodoxamide; et (c) de l'eau stérile.
PCT/US1996/010810 1995-06-29 1996-06-25 Combinaison d'antihistamines nasales topiques et de stabilisateurs de mastocytes topiques par voie nasale WO1997001340A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61811/96A AU6181196A (en) 1995-06-29 1996-06-25 The combination of topical nasal antihistamines and topical nasal mast cell stabilizers

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US49681595A 1995-06-29 1995-06-29
US08/496,815 1995-06-29

Publications (1)

Publication Number Publication Date
WO1997001340A1 true WO1997001340A1 (fr) 1997-01-16

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ID=23974255

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/010810 WO1997001340A1 (fr) 1995-06-29 1996-06-25 Combinaison d'antihistamines nasales topiques et de stabilisateurs de mastocytes topiques par voie nasale

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AU (1) AU6181196A (fr)
WO (1) WO1997001340A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030331A1 (fr) * 2003-09-26 2005-04-07 Fairfield Clinical Trials, Llc Traitement antihistaminique combine
EP1852123A3 (fr) * 1999-12-24 2008-09-10 The Mathilda And Terence Kennedy Institute Of Rheumatology Inhibition du système immunitaire par des inhibiteurs de NFkappaB
WO2013068876A1 (fr) * 2011-11-08 2013-05-16 Micro Labs Limited Procédés et compositions pour traiter une allergie oculaire
US20130324507A1 (en) * 2012-06-05 2013-12-05 Bioprojet Novel (aza)Benzhydryl Ether Derivatives, Their Process of Preparation and Their Use as H4-Receptor Ligands for Therapeutical Applications

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
N. CHAND ET AL.: "Inhibition of histamine release from rat peritoneal mast cells by azelastine. Interaction with selected antiasthmatic drugs", INT. ARCH. ALLERGY APPL. IMMUNOL., vol. 86, no. 3, 1988, pages 256 - 260, XP000601198 *
N. MYGIND: "Progress in the drug management of allergic rhinitis", EUR. ARCH. OTO-RHINO-LARYNGOL., vol. 252, no. Sup1, 1995, pages S68 - S72, XP000601255 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1852123A3 (fr) * 1999-12-24 2008-09-10 The Mathilda And Terence Kennedy Institute Of Rheumatology Inhibition du système immunitaire par des inhibiteurs de NFkappaB
US7915009B2 (en) 1999-12-24 2011-03-29 The Mathilda And Terence Kennedy Institute Of Rheumatology Trust Activation and inhibition of the immune system
WO2005030331A1 (fr) * 2003-09-26 2005-04-07 Fairfield Clinical Trials, Llc Traitement antihistaminique combine
WO2013068876A1 (fr) * 2011-11-08 2013-05-16 Micro Labs Limited Procédés et compositions pour traiter une allergie oculaire
US20130324507A1 (en) * 2012-06-05 2013-12-05 Bioprojet Novel (aza)Benzhydryl Ether Derivatives, Their Process of Preparation and Their Use as H4-Receptor Ligands for Therapeutical Applications
US9242959B2 (en) * 2012-06-05 2016-01-26 Bioprojet (Aza)benzhydryl ether derivatives, their process of preparation and their use as H4-receptor ligands for therapeutical applications

Also Published As

Publication number Publication date
AU6181196A (en) 1997-01-30

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