WO1997001340A1

WO1997001340A1 - The combination of topical nasal antihistamines and topical nasal mast cell stabilizers

Info

Publication number: WO1997001340A1
Application number: PCT/US1996/010810
Authority: WO
Inventors: Eileen Helzner
Original assignee: McNeil PPC Inc
Current assignee: Kenvue Brands LLC
Priority date: 1995-06-29
Filing date: 1996-06-25
Publication date: 1997-01-16
Anticipated expiration: 1997-12-29
Also published as: AU6181196A

Abstract

Nasal spray or nasal drops for the treatment of allergic rhinitis are disclosed comprising: a. an effective amount of a topical antihistamine to relieve histamine mediated symptoms where said topical nasal antihistamine is selected from the group consisting of azelastine and azatadine; b. an effective amount of a topical mast cell stabilizer to inhibit mast cell mediator release where said topical nasal mast cell stabilizer is selected from the group consisting of cromolyn sodium, nedocromil and lodoxamide; and c. sterile water.

Description

THE COMBINATION OF TOPICAL NASAL ANTIHISTAMINES AND TOPICAL NASAL MAST CELL STABILIZERS

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.

BACKGROUND OF THE INVENTION

Seasonal allergic 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. In sensitive individuals, rhinitis symptoms develop which include puffy, sore eyes, sneezing, nasal congestion, sinus headaches and fatigue.

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. 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. However, 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. Also employed to treat allergic rhinitis are mast cell stabilizers. In response to a challenge by an allergen, 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.

SUMMARY OF THE INVENTION

There is provided by the present invention a nasal spray or nasal drops for the treatment of allergic rhinitis comprising:

a. an effective amount of a topical antihistamine to relieve histamine mediated symptoms where said topical nasal antihistamine is selected from the group consisting of azelastine and azatadine;

b. an effective amount of a topical mast cell stabilizer to inhibit mast cell mediator release where said topical nasal mast cell stabilizer is selected from the group consisting of cromolyn sodium, nedocromil and lodoxamide; and

c. sterile water.

DETAILED DESCRIPTION OF THE INVENTION

The topical antihistamines herein are potent H¹ receptor antagonists which relieve the histamine mediated symptoms, i.e. sneezing, runny nose, itchy nose, etc. The H¹ receptor antagonists block the receptor sites and thereby block the expression of the histamine effect. Thus, persons skilled in the art understand that only a sufficient amount of the antihistamine should be administered to relieve histamine mediated symptoms and no more. This amount will vary depending on whether 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. 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. To achieve these dosage ranges, 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. Similarly, 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. Person skilled in the art understand that only a sufficient amount of mast cell stabilizer should be administered to inhibit mast cell mediator release and no more. This amount will vary depending on whether 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. In the case of 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. Likewise, in the case of 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. To achieve these dosage ranges, 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. Similary, 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 [Ca²⁺]j upon antigenic stimulation of the cell. Hence, it prevents histamine release. It has also been shown to inhibit degranulation and the antigen-induced ⁴⁵Ca²⁺-influx to a certain degree (Cox, Nature, 216:1328 (1967); Mazurek, et al., Nature, 303:528(1983)). The manufacture of cromolyn is well known and has been described by Fitzmaurice, Lee, Brit. Pat. 1 ,144, 906.

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 HPθ4²7H2Pθ4"- 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 absoφtion by the nasal mucosa and include polyoxyl 40 stearate, polyoxyethylene 50 stearate, polysorbate 80 and octoxynol.

In general, the concentration of the additives will be in the range as follows:

Additive % W/V

antimicrobial agent 0.001 - 2.0 antioxidant 0.01 - 0.20 isotonic agent 0.01 - 0.50 solubilizing agents 0.01 - 1.0 viscosity builders 0.1 - 2.0 surface active agents 0.01 - 1.0 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.

Claims

WHAT IS CLAIMED IS:

1. Nasal spray or nasal drops formulation comprising:

c. sterile water.

2. The formulation of claim 1 wherein said antihistamine is azelastine and said mast cell stabilizer is selected from the group consisting of cromolyn sodium, nedocromil and lodoxamide.

3. The formulation of claim 1 wherein said antihistamine is azatadine and said mast cell stabilizer is selected from the group consisting of cromolyn sodium, nedocromil and lodoxamide.

4. The formulation of claim 1 wherein said azelastine constitutes of the nasal spray or nasal drops composition from about 0.2 to about 40 mg/ml and said azatadine constitutes of the nasal spray or nasal drops composition from about 0.2 to about 40 mg/ml.

5. The formulation of claim 1 wherein said cromolyn sodium constitutes of the nasal spray or nasal drops composition from about 2 to about 80 mg/ml; said nedocromil constitutes from about 1 to about 80 mg/ml; and said lodoxamide constitutes from about 1 to about 100 mg/ml.