MXPA00002195A - Use of combinations comprising non-sedating antihistamines and alpha-adrenergic drugs for the topical treatment of rhinitis/conjunctivitis and cold, cold-like and/or flu symptoms - Google Patents

Abstract

Pharmaceutical combination, applicable topically, containing a non-sedating antihistamine in combination with an a-adrenergic agonist and optionally conventional physiologically acceptable carriers, diluting agents and auxiliaries substances for the prophylaxis and treatment of allergic and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or flu symptoms are claimed.

Description

USE OF COMBINATIONS THAT COMPRISE ANTIHISTAMINIC NO SEDATIVES AND ALPHA-ADRENERGIC DRUGS FOR THE TOPICAL TREATMENT OF RHINITIS / CONJUNCTIVITIS AND COLD, FLU SYMPTOMS AND / OR COLD TYPE TECHNICAL FIELD The present invention relates in general to new pharmaceutical compositions comprising "topical decongestants", preferably epinephrine, phenoxasoline, indazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazolin, tetrizolin, tramazoline, thimazoline or xylometazoline and a non-sedating antihistamine. , topically applicable such as levocabastine, efletirizine, but preferably azelastine The combinations are useful in the management of allergic and / or vasomotor rhinitis, conjunctivitis, cold, flu symptoms and / or cold.

BACKGROUND OF THE INVENTION In industrialized countries, more than 10-15% of the population suffers from rhinitis and / or allergic conjunctivitis. Rhinitis and / or allergic conjunctivitis are type I allergic responses that are measured by IgE antibodies. As part of an allergic response to the antigen, reaginic antibodies (IgE) are generated and bound to the surface of mast cells and basophils via the high affinity Fc receptors (FceRI) that are specific for IgE. Antigen that cross-links to IgE molecules leads to cellular responses comprising the release of executed mediators (e.g., histamines), formation and release of lipid mediators, and cytokine generation. The mast cells with their mediators can be considered as central to the initiation and mediation of the early phase of allergic inflammation. The symptoms of rhinitis are sneezing, itching (nasal irritation), rhinorrhea (runny nose), and nasal blockage (congestion). Nasal blockage is the result of the combination of blood in the capacitance vessels of the mucosa, and some degree of tissue edema outcome. Patients with allergic conjunctivitis show similar symptoms. Itching, rubbing of eyes and tears are very common, and cause much affliction. Conjunctival edema and hyperemia cause the bulbar surface to take on a "glassy" appearance, with dilated blood vessels. The common cold is usually not a serious illness, but it is a highly prevalent, uncomfortable and annoying affliction. The term "common cold" is applied to minor diseases of the upper respiratory system caused by a variety of different respiratory viruses, where rhinoviruses are the main known cause of the common cold. Symptoms such as nasal discharge, nasal blockage, and sneezing usually begin on the first day of illness and progress to maximum haste by the 2nd. and 3rd day. Along with nasal symptoms may come other symptoms such as cough, burning eyes, migraine. There may also be fever. Antihistamines are generally used in the symptomatic treatment of these disorders. They are effective in reducing itching, sneezing and watery discharge. Based on the down-regulating effect of azelastine on ICAM-1 (rhinovirus binding site), they may be particularly useful in the treatment of common cold / flu. In general, antihistamines are less effective in reducing nasal congestion (blockage). To achieve further reduction of nasal congestion and ocular edema, a-adrenergic agonists are often used either alone or in combination with antihistamines.

Non-sedating antihistamines, especially those administered topically, represent a new generation of histamine receptor antagonists Hi. They possess strong antagonistic activity to the Histamine histamine receptors without causing sedation. For example, azefastin, a derivative of phthalazinone, corresponds to these non-sedating antihistamines, called second generation. It is characterized by a prolonged anti-allergic activity and shows a broad aspect of pharmacological activities that do not include only the antagonism of the histamine-H receptorbut also inhibition of histamine release followed by stimulation with the antigen and not antigen (Chandi N. et al.) Inhibition of allergic and nonallergic leu otriene C4-formation and histamine secretion by azelastine: Implication for its mechanism of action. Arch. Allergy Appl. Immunol. 90: 67-70, 1989). Recently, it has also been shown that topically administered azelastine downregulates ICAM-1 (intracellular adhesion molecule-1), the binding site for rhinoviruses (Ciprandi, MD et al Topical azelastine reduces eosinophil activation and intracellular adhesion molecule- 1 expression on nasal cells: An antiallergic activity, J. Allergy Clin.Immunol.98: 1088-1096, 1996). Azelastine is free of cardiovascular side effects. Because the drug is administered topically, plasma levels after topical application of azelastine are extremely low, even if overdosed. In contrast, oral formulations containing second generation antihistamines such as terfenadine, astemizole, loratadine may elicit cardiovascular side effects (e.g., tachyarrhythmias) when the recommended dose is not maintained. With respect to allergic diseases and the common cold, either a-adrenergic agonists either topically or orally are used as described in WO 94/08551. Oral decongestants (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine as described in for example, WO 92/04021, WO 92/04022, WO 94/08550, WO 94/14449 and WO 95/23591) have the risk of inducing effects systemic adverse events such as tachycardia, increased blood pressure, and CNS stimulation (eg, insomnia). Topical α-adrenergic agonists such as epinephrine, phenoxazoline, indanazoline, nefazoline, oxedrine, oxymetazoline, phenylephrine, tefazolin, tetrizolin, tramazoline, thiazoline, xylometazoline are used as local decongestants in patients with allergic or vasomotor rhinitis, conjunctivitis, or with infections upper respiratory tract (for example, common cold, flu). The a-adrenergic drugs probably decrease the resistance to airflow by decreasing the volume of the nasal mucosa. This can occur by the activation of a-adrenergic receptors in the venous capacitance vessels of the nasal tissues. Topical decongestants are particularly useful because of their more selective site of action. Although its topical administration is associated with few systemic adverse effects, and prolonged use may result in rebound congestion and worsening of symptoms. Therefore, the use of formulations containing a nasal vasoconstrictor compound is not recommended for more than 7-10 days. In addition, the recommended daily dose should not be exceeded. For oral use, combinations containing antihistamines and α-adrenergic agonists are widely used both for the treatment of allergic rhinitis and the common cold as described in WO 88/09656, WO 94/14476, WO 94/25009 and WO 07/95/103 It has been shown that patients suffering from common cold or allergic rhinitis have a benefit from decongestant therapy with oral antihistamines (Anonymus, The management of hay fever, Drug Ther, Bull, 23: 25-27, 1985).; Berkowitz, R.B. et al. The effectiveness of the nonsedating antihistamine loratadine plus pseudoephedrine in the symptomatic management of the common cold. Ann Allergy 63: 336-339, 1989). Topical α-adrenergic agonists in combination with antihistamines are administered in which sedating antihistamines (eg, antazoline) are used. Topical formulations containing second generation antihistamines and α-adrenergic agonists are not available and are unknown at the present time. Topical decongestants (a-adrenergic agonists) provide rapid release of nasal and ocular edema. Therefore, they could improve the therapeutic effectiveness of topically applied antihistamines such as azelastine. Formulations for cold treatment, cold and / or cold-like symptoms often contain antihistamines and decongestants. So far, only oral combination preparations are on the market. The therapeutic activity of a non-sedating antihistamine, applied topically as for example azelastine, a histamine Hi receptor agonist that can effectively withstand a-adrenergic agonists without increasing the risk of adverse effects.

BRIEF DESCRIPTION OF THE INVENTION Therefore, it is an object of the present invention to provide pharmaceutical combinations of subject matter, applicable topically, comprising an effective non-sedating antihistamine amount, preferably acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizine, epinastine, fexofenadine, loratidine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine in combination with an α-adrenergic agonist, preferably epinephrine, fenoxazoline, indazoline, nefazoline, oxedrine, oxymetazoline, phenylephrine, tefazolin, tetrizolin, tramazoline, thimazoline or xylometazoline and which optionally includes pharmaceutically acceptable carriers and / or diluents or auxiliary substances therefor. It is a further object of the present invention to provide a method for the prophylaxis and treatment of allergic and / or vasomotor rhinitis, conjunctivitis, cold, flu symptoms and / or cold type in a mammalian organism in need of treatment by topical administration of a safe and effective amount of a combination comprising a non-sedating antihistamine, preferably acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizin, epinastine, fexofenadine, loratidine, levocabastine, mizolastin, oxatomide, setastine, temelastin or terfenadine with an α-adrenergic agonist, preferably epinephrine, phenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetrizoline, tramazoline, ti-azoline or xylometazoline. It is another object of the present invention to provide dosage unit forms, suitable for a non-sedating antihistamine, preferably acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizin, epinastine, fexofenadine, loratidine, levocabastine, mizolastin, oxatomide, setastine, temelastin. or terfenadine in combination with an α-adrenergic agonist, preferably epinephrine, phenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetrizolin, tramazoline, thimazoline or xylometazoline, adapted for convenient topical administration, for example, in the form of Sprays or drops.

DETAILED DESCRIPTION OF THE INVENTION The anti-allergic component in the pharmaceutical combination of the present invention includes a non-sedative antihistamine applied topically for example acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizin, epinastine, fexofenadine, loratidine, levocabastine, mizolastine. , oxatomide, setastine, temelastin or terfenadine or a pharmaceutically acceptable salt thereof. Azelastine is a second-generation histamine-Hi receptor agonist with no sedative effect. The antihistamine component concentration of the present invention can vary from 0.001% to 0.5%. In addition to the antihistamine component, the pharmaceutical combinations of the present invention comprise a topical decongestant, preferably epinephrine, phenoxazoline, indanazoline, nefazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetrizoline, tramazoline, thimazoline or xylometazoline, or a pharmaceutically acceptable salt thereof. . The concentration of a-adrenergic agonists in the combination can vary from 0.001% to 0.2%. The concentration of phenylephrine can vary, however from 0.01% to 15%, its preferred concentration is between 0.1% to 2%. The preferred concentrations are for the antihistamine component of 0.05% - 0.1% and for the α-adrenergic agonists of 0.05% - 0.1%, with the exception of phenylephrine (its preferred concentration see above). The active ingredients are administered topically as a mixture containing pharmaceutical diluents, excipients or carriers that are consistent in conventional pharmaceutical practices. As representative representative formulations, consistent with the objects, features and advantages of the invention, the following examples are provided.

Dosage The pharmaceutical combination is administered as a rule, for the nasal application: 1 a breath / nostril twice daily; maximum daily dose 3 puffs / nostril and for eye application: 1 drop / eye twice a day, maximum daily dose 3-6 drops / eye. These compositions for topical applications can be formulated in various pharmaceutically acceptable forms, for example, as nasal sprays or nasal drops or as eye drops. In addition to the active ingredients, the compositions of the present invention may further comprise various ingredients such as antimicrobial preservatives, tonicity agents, thickening agents, excipients for pH adjustment or buffering agents. For example, antimicrobial preservatives may include: benzalkonium chloride, chlorobutanol, thiomersal, methylparaben, propylparaben, sorbic acid, edetate disodium, phenylethanol, chlorexadine-HCl, chlorhexadine acetate, chlorhexadine digluconate, chloride / cetylpyridinium bromide, chlorocresol, acetate of phenyl mercury, phenylmercury nitrate, phenylmercury borate, phenoxyethanol. For storage, a combination of disodium edetate and benzalkonium chloride is preferably used. Disodium edetate is used in concentrations of 0.05-0.1% and benzalkonium chloride in concentrations of 0.005-0.05%. Suitable excipients that can be used to adjust the tonicity or osmolarity can include: sodium chloride, potassium chloride, mannitol, glucose, sorbitol, glycerol, propylene glycol. In general, these agents are used in concentrations of about 0.1 to 10%. The compositions often contain thickening agents to increase viscosity and prolong drug contact in the tissue. These thickening agents can be: methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylates, polyacrylamide, dextran, gellan gum (Gelrite "), poloxamer, cellulose acetate phthalate, The compositions of the present invention. they also include sufficient pharmaceutically acceptable buffers to adjust and maintain the pH in the range of about 4 to 8, preferably about 5.5 to 7.5. Suitable buffers are citrate, phosphate, tromethamine, glycine, borate, acetate. of substances such as citric acid, monosodium phosphate, disodium phosphate, glycine, boric acid, sodium tetraborate, acetic acid, sodium acetate, etc. Other excipients for pH adjustment such as hydrochloric acid or sodium hydroxide can also be used. give further details in this invention by the following exemplary entities that should not be limitations within the scope of the present invention.

EXAMPLE 1 Nasal spray and nasal drops containing Azelastine-HCl (0.1%) and Oximetazoline-HC (0.05%). ml of solution contain: EXAMPLE 2 Eye drops containing Azelastine-HCl (0.05%) and Tetrizoline-HCl (0.05%) EXAMPLE 3 Nasal spray or nasal drops.

See example 1, but with 0.1% of Xylometazoline-HCl instead of 0.05% Oxymetazoline-HC1.

EXAMPLE 4 Drops for eyes See example 2, but with 0.1% Naphazoline-HC1 instead of 0.05% Tetrizoline-HCl.

EXAMPLE 5 Nasal spray or nasal drops See example 1, but with 0.05% Naphazoline-HC1 instead of 0.05% Oximetazoline-HCl EXAMPLE 6 Nasal spray or nasal drops See Example 1, but with 0.1264% of Tramazoline-HCl instead of 0.05% of Oximetazoline-HC1.

EXAMPLE 7 Drops for eyes.

See example 2, but with 0.0632% of Tramazoline-HCl instead of 0.05% of Tetrizolina-HCl Preparation of eye drops (Example 2, 4 and 7): Prepare 45.0 kg of water for injection in a suitable container and dissolve in it while stirring: The active ingredients, disodium edetate, benzalkonium chloride, hydroxypropyl methylcellulose and sorbitol solution. Fill the solution with water for injection to 49.5 liters. Adjust the pH of the solution with sodium hydroxide solution IN to pH6. Fill the solution with water for injection to obtain 50.0 liters and shake. Filter sterile function through a membrane filter, with a pore size of 0.2 μm. Fill the solution aseptically in sterilized bottles.

Preparation of nasal sprays and nasal drops (Example 1, 3, 5 and 6) Prepare 96.5 kg of purified water in a suitable container and dissolve in it while stirring: The active ingredients, disodium edetate, sorbitol solution, benzalkonium chloride, disodium phosphate dodecahydrate, anhydrous citric acid and hydroxypropyl methylcellulose. Fill the solution to 100 liters and shake. Filter the solution through a membrane filter in a pore size of 0.2 μm and fill in bottles.

Claims (18)

1. CLAIMS: 1. A pharmaceutical combination of material for use in the treatment of allergic and / or vasomotor rhinitis, conjunctivitis, colds, cold and / or cold symptoms, and adapted for topical administration in unit doses, the combination comprises : a) an effective amount of a non-sedating antihistamine or a pharmaceutically acceptable salt thereof, b) an effective amount of an alpha-adrenergic agonist or a pharmaceutically acceptable salt thereof, and c). physiologically acceptable, conventional carriers and / or diluting agents or auxiliary substances.
2. 2. The pharmaceutical combination according to claim 1, the non-sedating antistamines comprising acrivastine, antasoline, astenizole, azelastine, cetirizine, ebastine, efletirizin, epinastine, fexofenadine, loratidine, levocavastin, mizolastin, oxatomide, setastine, temelastin or terfenadine.
3. 3. The pharmaceutical combination according to claim 1, the α-adrenergic agonists comprising epinephrine, phenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetrizolin, tramazoline, thimazoline or xylometazoline.
4. 4. The pharmaceutical combination according to claim 1 and 2, comprising .001% to 0.5% of the antihistaminic component.
5. 5. The pharmaceutical combination according to claims 1, 2 and 4, which preferably comprises 0.05% to 0.1% of the antihistamine component.
6. 6 The pharmaceutical combination according to claims 1 and 3, comprising 0.001% to 0.2% of the α-adrenergic agonist, with the exception of phenylephrine.
7. 7. The pharmaceutical combination according to claims 1, 3 and 6, which preferably comprises 0.05% to 0.1% of α-adrenergic agonist, with the exception of phenylephrine.
8. 8. The pharmaceutical combination according to claims 1 and 3, comprising 0.01% to 15% phenylephrine.
9. 9. The pharmaceutical combination according to claims 1, 3 and 8, which preferably comprises 0.1% to 2% phenylephrine.
10. 10. The pharmaceutical combination as defined by claims 1 to 9, in the form of topical dose.
11. 11. The pharmaceutical combination according to claims 1 to 10, in the form of a topical dose aerosol.
12. 12. The pharmaceutical combination as defined by claims 1 to 10, in the form of topical dose drops.
13. 13. The use of a pharmaceutical combination of matter, comprising: a) an effective amount of a non-sedating antihistamine or a pharmaceutically acceptable salt thereof, b) an effective amount of an α-adrenergic agonist or a pharmaceutically acceptable salt thereof , and c) physiologically acceptable, conventional carriers and / or diluents or auxiliary substances, j for the production of a medicament for the prophylaxis and treatment of allergic and / or vasomotor rhinitis, conjunctivitis, cold, cold and / or cold symptoms , by topical administration.
14. 14. The use of a pharmaceutical combination of matter according to claim 13, the non-sedating antihistamine comprising acrivastine, antasoline, astenizol, azelastine, cetirizine, ebastine, efletirizin, epinastine, fexofenadine, loratidine, levocavastin, mizolastin, oxatomide, setastine, temelastin or terfenadine. , for the production of a medicament for the prophylaxis and treatment of allergic and / or vasomotor rhinitis, conjunctivitis, cold, flu symptoms and / or cold type, by topical administration.
15. The use of a pharmaceutical combination of matter according to claim 13, wherein the α-adrenergic agonist comprises epinephrine, phenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetrizolin, tramazoline, thimazoline or xylometazoline for the production of a medicine for the prophylaxis and treatment of allergic and / or vasomotor rhinitis, conjunctivitis, cold, symptoms of flu and / or type cold, by topical administration.
16. 16. Medicaments for topical administration that have action against allergic and / or vasomotor rhinitis, conjunctivitis, cold, cold and / or flu-like symptoms, comprising: a) an effective amount of a non-sedating antihistamine or a pharmaceutically acceptable salt thereof, b) an effective amount of an α-adrenergic agonist or a pharmaceutically salt acceptable thereof, and c) physiologically acceptable, conventional carriers and / or diluents or auxiliaries.
17. 17. Medicaments according to claim 16, wherein the non-sedating antihistamine comprises acrivastine, antasolin, astenizol, azelastine, cetirizine, ebastine, efletirizin, epinastine, fexofenadine, loratidine, levocavastin, mizolastin, oxatomide, setastine, temelastin or terfenadine.
18. 18. Medicaments according to claim 16, wherein the a-adrenergic agonist comprises epinephrine, phenoxazoline, indanazoline, nefazolin, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetrizolin, tramazoline, thimazoline or xylometazoline.