Indian Patents. 209250:PHARMACEUTICAL COMBINATIONS COMPRISING NONSEDATING ANTIHISTAMINES AND A-ADRENERGIG DRUG FOR THE TOPICAL TREATMENT OF RHINITIS/CONJNUCTIVITIS AND COLD, COLD-LIKE AND/OR FLU SYMPTOMS.

Title of Invention	PHARMACEUTICAL COMBINATIONS COMPRISING NONSEDATING ANTIHISTAMINES AND A-ADRENERGIG DRUG FOR THE TOPICAL TREATMENT OF RHINITIS/CONJNUCTIVITIS AND COLD, COLD-LIKE AND/OR FLU SYMPTOMS.
Abstract	Pharmaceutical combination, applicable topically, containing a non-sedating antihistamine in combination with an -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.

Full Text	1A Use of combinations comprising non-sedating antihistamines and -adrenergic drugs for the topical treatment of rhinitis/conjunctivitis and cold, cold-like and/or flu symptoms Technical field The present invention relates generally to novel pharmaceutical compositions containing , topical decongestants", preferably epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoline or xylometazoline and a non-sedating antihistamine, applicable topically such as levocabastine, efletirizine, however preferably azelastine. The combinations are useful in the management of allergic and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or flu symptoms. Background of the invention In industrialized countries, more than 10-15 % of the population suffer from alleraic rhinitis and/or conjunctivitis. Allergic rhinitis and/or conjunctivitis are type I allergic responses that are mediated by IgE antibodies. As a part of an allergic response to antigen, reaginic antibodies (IgE) are generated and bound to the surface of mast cells and basophils via high affinitiy Fc receptors (Fc RI) that are specific for IgE. Antigen cross-linking the lgE-molekules leads to cellular responses involving release of performed mediators (e.g. histamine), lipid mediator formation and release, and cytokine generation. Mast cells with their mediators can be regarded as central to the initiation and mediation of the early phase of allergic inflammation. Symptoms of rhinitis are sneezing, itching (nasal irritation), rhinorrhea (nasal secretion) and nasal blockage (congestion). Nasal blockage is the result of the pooling of blood in the capacitance vessels of the mucosa, and to some degree the result of tissue oedema. Patients with allergic conjunctivitis show similar symptoms. 2 Itching, eye rubbing and tearing are very common, and cause much distress. Conjunctival oedema 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 highly prevalent, discomforting, and annoying infliction. The term ,,common cold" is applied to minor upper respiratory illnesses caused by a variety of different respiratory viruses, in where rhinoviruses are the major known cause of common cold. Symptoms such as nasal discharge, nasal blockage, and sneezing usually commence on the first day of illness and progress to maximum severity by the 2nd and 3rd day. Along with nasal symptoms may come other symptoms such as cough, burning of the eyes, headache. Fever can also occur. Antihistamines are generally used in the symptomatic treatment of these disorders. They are effective in reducing itching, sneezing and watery secretion. Based on the ICAM-1(rhinovirus binding site) down-regulating effect of azelastine, it may be particularly useful in the treatment of common cold/flu. Antihistamines are, in general, less effective in the reduction of nasal congestion (blockage). To achieve a further reduction of nasal congestion and ocular oedema, a-adrenergic agonists are often used either alone or in combination with antihistamines. Non-sedating antihistamines especially such administered topically represent a new generation of histamine H1 receptor antagonists. They possess strong antagonistic activity at histamine H1 receptors without causing sedation. For example, azelastine, a phthalazinone derivative, belongs to this so-called second-generation, non-sedating antihistamines. It is characterized by a long-lasting antiallergic activity and shows a broad spectrum of pharmacologic activities including not only antagonism of histamine Hi-receptors but also inhibition of histamine release following antigen and non-antigen stimuli (Chand, N. et al. Inhibition of allergic and nonallergic leukotriene C4-formation and histamine secretion by azelastine: Implication for its mechanism of action. Int. Arch. Allergy Appl. Immunol. 90:67-70, 1989). Recently, it has also been demonstrated that topically administered azelastine down-regulates ICAM-1 (intercellular adhesion 3 molecule-1), the binding site for rhinoviruses (Ciprandi, M. D. et al. Topical azelastine reduces eosinophif activation and intraceilular 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, the plasma levels following topical azelastine application are extremely low, even if it is overdosaged. By contrast, oral formulations containing antihistamines of the second generation such as terfenadine, astemizole, loratadine may cause cardiovascular side effects (e.g. tachyarrhythmias) when the recommended dosage is not kept. With regard to allergic diseases and common cold, either topical or oral a-adrenergic agonists are used as disclosed in WO 94/ 08551. Oral decongestants (e.g. pseudoephedrine, phenylephrine, phenylpropanolamine as disclosed in, for example, WO 92/ 04021, WO 92/ 04022, WO 94/ 08550, WO 94/14449 and WO 95/ 23591) carry the risk of inducing systemic adverse effects such as tachycardia, increased blood pressure, and CNS stimulation (e.g. insomnia). Topical a-adrenergic agonists such as epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoline, xylometazoline are used as local decongestants in patients with allergic or vasomotor rhinitis, conjunctivitis or with upper respiratory infections (e.g. common cold, flu). a-Adrenergic drugs probably decrease resistance to airflow by decreasing the volume of the nasal mucosa. This may occur by activation of a-adrenergic receptors in venous capacitance vessels in nasal tissues. Topical decongestants are particularly useful because of their more selective site of action. Although their topical administration is associated with few systemic adversed effects, prolonged use may result in rebound congestion and worsening of symptoms. Therefore, the use of formulations containing a nasal vasoconstrictor compound is not recommended longer than 7-10 days. In addition, the recommended daily dosage should not be exceeded. For oral use, combinations containing antihistamines and a-adrenergic agonists are widely used both for the treatment of allergic rhinitis and common cold as disclosed in WO 88/ 09656, WO 94/14476, WO 94/ 25009 and WO 95/ 07103. It has been 4 demonstrated that patients suffering from common cold or allergic rhinitis have benefit from oral antihistamine + decongestant therapy (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 a-adrenergic agonists in combination with antihistamines are administered in which sedating antihistamines(e.g. antazoline) are used. Topical formulations containing antihistamines of the second generation and a-adrenergic agonists are not available and unknown at the moment Topical decongestants (a-adrenergic agonists) provide quick relief of nasal or ocular oedema. Therefore, they could improve the therapeutic effectiveness of topically applied antihistamines such as azelastine. Formulations for the treatment of cold, cold-like and/or flu symptoms often contain antihistamines and decongestants. Until now, only oral combination preparations are on the market. The therapeutic activity of a non-sedating antihistamine, applied topically as for instance azelastine, a histamine Hi-receptor antagonist can effectively be supported by a-adrenergic agonists without increasing the risk of adverse effects. Summary of the invention It is therefore an object of the present invention to provide pharmaceutical combinations of matter, applicable topically, comprising an effective amount of a non-sedating antihistamine, preferably acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizine, epinastine, fexofenadine, loratidine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine in combination with an a-adrenergic agonist, preferably epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoline or xylometazoline and further optionally including pharmaceutically acceptable carriers and/or diluting agents or auxiliary substances therefor. 5 It is an additional object of the present invention to provide a method for the prophylaxis and treatment of allergic and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or flu symptoms in a mammalian organism in need of such treatment by topical administering a safe and effective amount of a combination comprising a non-sedating antihistamine, preferably acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizine, epinastine, fexofenadine, loratidine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine with an -adrenergic agonist, preferably epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoline or xylometazoline. It is another object of the present invention to provide suitable dosage unit forms of a non-sedating antihistamine, preferably acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizine, epinastine, fexofenadine, loratidine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine in combination with an -adrenergic agonist, preferably epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazofine, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoiine or xylometazoline, adapted for convenient topical administration, for instance, in the form of sprays or drops. Detailed description of the invention The antiallergic component in the pharmaceutical combination of the present invention includes a non-sedating antihistamine applied topically as for instance acrivastine, antazoline, astemizole, azelastine cetirizine, ebastine, efletirizine, epinastine, fexofenadine, loratidine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine or a pharmaceutically acceptable salt thereof. Azelastine is a histamine Hi-receptor antagonist of the second generation without sedating effect. The concentration of the antihistaminic component of the present invention may range from 0.001% to 0.5%. 6 In addition to the antihistaminic component the pharmaceutical combinations of the present invention comprise a topical decongestant, preferably epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoline or xylometazoline, or a pharmaceutically acceptable salt thereof. The concentration of a-adrenergic agonists in the combination may range from 0.001% to 0.2%. The concentration of phenylephrine may however range from 0,01% to 15%, its preferred concentration is between 0.1% to 2%. The preferred concentrations are for the antihistaminic component 0.05% - 0.1% and for a-adrenergic agonists 0.05% - 0.1%, with exception of phenylephrine (its preferred concentration see above). The active ingredients are administered topically as a mixture containing pharmaceutical diluents, excipients or carrier which are consistent with conventional pharmaceutical practices. As representative suitable formulations consistent with the objects, features and advantages of the invention, the following examples are provided. Dosages: The pharmaceutical combination is administered as a rule, for nasal application :1 puff/nostril twice daily; maximum daily dose 3 puffs/nostril and for ocular application: 1 drop/eye twice daily, maximum daily dose 3-6 drops/eye. The compositions for topical applications can be formulated in various pharmaceutically acceptable forms e.g. as nasal sprays or nasal drops or as eye drops. Besides 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 buffer systems. For example antimicrobial preservatives can include: benzalkonium chloride, chlorobutanol, thiomersal, methylparaben, propylparaben, sorbic acid, edetate disodium, phenylethanol, chlorhexidine HCI, chlorhexidine acetate, chlorhexidine digluconate, cetylpyhdinium chloride / bromide, chlorocresol, phenylmercuric acetate, phenylmercuric nitrate, phenylmercuric borate, phenoxyethanoi. For preservation preferably a combination of edetate disodium and benzalkonium chloride is used. Edetate disodium is used in concentrations of 0.05 - 0.1 % and benzalkonium chloride in concentrations of 0.005 - 0.05 %. Suitable excipients which can be used to adjust tonicity or osmolality 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 the viscosity and prolong contact of the drug with the tissue. Such thickening agents may be: methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylates, polyacrylamide, dextran, gellan gum (Gelrite®), poloxamere, cellulose acetate phthalate. The compositions of the present invention also include pharmaceutically acceptable buffers sufficient 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. These buffers can be built from substances like citric acid, monosodium phosphate, disodium phosphate, glycine, boric acid, sodium tetraborate, acetic acid, sodium acetate. Also other excipients can be used for pH-adjustment like hydrochloric acid or sodium hydroxide. Further details of this invention are given by the following examples which should not be limitations to the scope of the present invention. 8 Example 1 Nasal spray or nasal drops containing Azelastine HCI (0.1%) and Oxymetazoline HC! (0.05%) Example 2 Eye drops containing Azelastine HCI (0.05%) and Tetryzoline HCI (0.05%) 10 ml solution contain: Example 3 Nasal spray or nasal drops See example 1 but with 0.1 % Xylomethazoline HCI instead of 0.05% Oxymethazoline HCI 9 Example 4 Eye drops See example 2 but with 0.1% Naphazoline HCi instead of 0.05% Tetryzoline HCl Example 5 Nasal spray or nasal drops See example 1 but with 0.05% Naphazotine HCI instead of 0.05% Oxymethazoline HCI Example 6 Nasal spray or nasal drops See example 1 but with 0.1264 % Tramazoline HCI instead of 0.05 % Oxymethazoline HCI Example 7 Eye drops See example 2 but with 0.0632% Tramazoline HCI instead of 0.05% Tetryzoline HCI Preparation of eye drops (Example 2, 4 and 7): Prepare 45.0 kg of water for injections in a suitable container and dissolve therein while stirring: 10 the active principles, edetate disodium, benzalkonium chloride, hydroxypropyi methylceilulose and sorbitol solution. Fill up the solution with water for injection to 49.5 litres. Adjust the pH of the solution with sodium hydroxyde solution 1N to pH 6. Fill up the solution with water for injections to get 50.0 litres and stir. Sterile-filter the solution through a membrane filter, pore size 0.2 urn. Fill the solution aseptically into sterilised bottles. Preparation of nasal sprays or nasal drops (Example 1, 3, 5 and 6) Prepare 96.5 kg of purified water in a suitable container and dissolve therein while stirring: the active principles, edetate disodium, sorbitoi solution, benzalkonium chloride, disodium phosphate dodecahydrate, citric acid anhydrous and hydroxypropyi methylcellulose. Fill up the solution to 100 litres and stir. Filter the solution through a membrane filter of pore size 0.2 m and fill it into bottles. -11- WE CLAIM: 1. A pharmaceutical combination of matter for use in the treatment of allergic and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or flu symptoms, and adapted for unit dosage topical administration, said combination comprising a) 0.001% to 0.5% of a non-sedating antihistamine or a pharmaceuticalfy acceptable salt thereof, b) 0.001% to 0,2% of an -adrenergic agonist or a pharmaceutically acceptable salt thereof with the exception of phenylephrine or 0.01 to 15% of phenylephrine; c) conventional physiologically acceptable carriers and/or diluting agents or auxiliary substances. 2. The pharmaceutical combination as claimed in claim 1, said non-sedating antihistamines comprising acrivastine, antazoline, astemizole, azelastine, cetirizing, ebastine , efletirizine, epinastine, fexofehadine, loratidine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine. -12- 3. The pharmaceutical combination as claimed In claim 1, said -adrenergic agonists comprsing epinephrine, fenoxazopline, indanazoline, naphazoiine, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoline orxylometazoline. 4. The pharmaceutical combination as claimed in claims 1,2 and 4, comprising preferably 0.05% to 0.1% of the antlhistamlnic component. 5. The pharmaceutical combination as claimed in claims 1,3 an 6, comprising preferably 0.05% to 0.1% of -adrenergic agonist, with the exception of phenylephrine. 6. The pharmaceutical combination as claimed in claims 1,3 and 8, comprising preferably 0.1% to 2% of phenylephrine. 7. The pharmaceutical combination as claimed in claims 1 to 9 in topical dosage form. 8. The pharmaceutical combination as claimed in claims 1 to 10 in topical dosage spray form. 9. The pharmaceutical combination as claimed in claims 1 to 10 in topical dosage drop form. -13- 10. 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 -adrenerglc agoist or a pharmaceutically acceptable salt thereof and c) conventional physiologically acceptable carriers and/or diluting agents or auxiliary substances. For the production of a medicament for the prophylaxis and treatment of allergic and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or flu symptoms by topical administration. 11. A pharmaceutical combination of matter as defined by claim 13, said non-sedating antihistamine comprising acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizined, epinastine, fexofenadine, loratidine, levocabastine, mizolastine , oxatomide, setastine, lemelastine or terfenadine, for the production of a medicament for the prophylaxis and treatment of allergic and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or flu symptoms, by topical administration. -14- 12. A pharmaceutical combination of matter as defined by claim 13, said -adrenergic agonist comprising epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymelazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazollne or xylometazoline for the production of a medicament for the prophylaxis and treatment of allergic and/or vasomotoric rhinrts, conjunctivitis, cold, cold-like and/or flu symptoms, by topical administration. 13, Medicaments for topical administration having action against allergic and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or or flu symptoms comprising a) an effective amount of a non-sedating antihistamine or a pharmaceutlcally acceptable salt thereof, b) an effective amount of an a-adrenergic agonist or a pharmaceutically acceptable salt thereof and c) conventional physiologically acceptable carriers and/or diluting agents or auxiliary substances. 17. Medicaments as claimed in claim 16, said non-sedating antihisfamine comprising acrivastine, antazoline, astemizole, azelastine, cetirrzine, ebastine, efletlrizine, eplnastine, fexofenadine, loratldine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine. ¦15- 13. Medicaments as claimed In claim 16, said -adrenergic agonist comprising epineprtrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoitne, phenylephrine, tefazoline, tetryzoline, tramazoline tymazoline or xylometazoline. Pharmaceutical combination, applicable topically, containing a non-sedating antihistamine in combination with an -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.

Full Text

1A
Use of combinations comprising non-sedating antihistamines and -adrenergic drugs for the topical treatment of rhinitis/conjunctivitis and cold, cold-like and/or flu symptoms
Technical field
The present invention relates generally to novel pharmaceutical compositions containing , topical decongestants", preferably epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoline or xylometazoline and a non-sedating antihistamine, applicable topically such as levocabastine, efletirizine, however preferably azelastine. The combinations are useful in the management of allergic and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or flu symptoms.
Background of the invention
In industrialized countries, more than 10-15 % of the population suffer from alleraic rhinitis and/or conjunctivitis. Allergic rhinitis and/or conjunctivitis are type I allergic responses that are mediated by IgE antibodies. As a part of an allergic response to antigen, reaginic antibodies (IgE) are generated and bound to the surface of mast cells and basophils via high affinitiy Fc receptors (Fc RI) that are specific for IgE. Antigen cross-linking the lgE-molekules leads to cellular responses involving release of performed mediators (e.g. histamine), lipid mediator formation and release, and cytokine generation. Mast cells with their mediators can be regarded as central to the initiation and mediation of the early phase of allergic inflammation.
Symptoms of rhinitis are sneezing, itching (nasal irritation), rhinorrhea (nasal secretion) and nasal blockage (congestion). Nasal blockage is the result of the pooling of blood in the capacitance vessels of the mucosa, and to some degree the result of tissue oedema. Patients with allergic conjunctivitis show similar symptoms.

2
Itching, eye rubbing and tearing are very common, and cause much distress. Conjunctival oedema 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 highly prevalent, discomforting, and annoying infliction. The term ,,common cold" is applied to minor upper respiratory illnesses caused by a variety of different respiratory viruses, in where rhinoviruses are the major known cause of common cold. Symptoms such as nasal discharge, nasal blockage, and sneezing usually commence on the first day of illness and progress to maximum severity by the 2nd and 3rd day. Along with nasal symptoms may come other symptoms such as cough, burning of the eyes, headache. Fever can also occur.
Antihistamines are generally used in the symptomatic treatment of these disorders. They are effective in reducing itching, sneezing and watery secretion. Based on the ICAM-1(rhinovirus binding site) down-regulating effect of azelastine, it may be particularly useful in the treatment of common cold/flu. Antihistamines are, in general, less effective in the reduction of nasal congestion (blockage). To achieve a further reduction of nasal congestion and ocular oedema, a-adrenergic agonists are often used either alone or in combination with antihistamines.
Non-sedating antihistamines especially such administered topically represent a new generation of histamine H1 receptor antagonists. They possess strong antagonistic activity at histamine H1 receptors without causing sedation. For example, azelastine, a phthalazinone derivative, belongs to this so-called second-generation, non-sedating antihistamines. It is characterized by a long-lasting antiallergic activity and shows a broad spectrum of pharmacologic activities including not only antagonism of histamine Hi-receptors but also inhibition of histamine release following antigen and non-antigen stimuli (Chand, N. et al. Inhibition of allergic and nonallergic leukotriene C4-formation and histamine secretion by azelastine: Implication for its mechanism of action. Int. Arch. Allergy Appl. Immunol. 90:67-70, 1989). Recently, it has also been demonstrated that topically administered azelastine down-regulates ICAM-1 (intercellular adhesion

3
molecule-1), the binding site for rhinoviruses (Ciprandi, M. D. et al. Topical azelastine reduces eosinophif activation and intraceilular 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, the plasma levels following topical azelastine application are extremely low, even if it is overdosaged. By contrast, oral formulations containing antihistamines of the second generation such as terfenadine, astemizole, loratadine may cause cardiovascular side effects (e.g. tachyarrhythmias) when the recommended dosage is not kept.
With regard to allergic diseases and common cold, either topical or oral a-adrenergic agonists are used as disclosed in WO 94/ 08551. Oral decongestants (e.g. pseudoephedrine, phenylephrine, phenylpropanolamine as disclosed in, for example, WO 92/ 04021, WO 92/ 04022, WO 94/ 08550, WO 94/14449 and WO 95/ 23591) carry the risk of inducing systemic adverse effects such as tachycardia, increased blood pressure, and CNS stimulation (e.g. insomnia). Topical a-adrenergic agonists such as epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoline, xylometazoline are used as local decongestants in patients with allergic or vasomotor rhinitis, conjunctivitis or with upper respiratory infections (e.g. common cold, flu). a-Adrenergic drugs probably decrease resistance to airflow by decreasing the volume of the nasal mucosa. This may occur by activation of a-adrenergic receptors in venous capacitance vessels in nasal tissues. Topical decongestants are particularly useful because of their more selective site of action. Although their topical administration is associated with few systemic adversed effects, prolonged use may result in rebound congestion and worsening of symptoms. Therefore, the use of formulations containing a nasal vasoconstrictor compound is not recommended longer than 7-10 days. In addition, the recommended daily dosage should not be exceeded.
For oral use, combinations containing antihistamines and a-adrenergic agonists are widely used both for the treatment of allergic rhinitis and common cold as disclosed in WO 88/ 09656, WO 94/14476, WO 94/ 25009 and WO 95/ 07103. It has been

4
demonstrated that patients suffering from common cold or allergic rhinitis have benefit from oral antihistamine + decongestant therapy (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 a-adrenergic agonists in combination with antihistamines are administered in which sedating antihistamines(e.g. antazoline) are used. Topical formulations containing antihistamines of the second generation and a-adrenergic agonists are not available and unknown at the moment Topical decongestants (a-adrenergic agonists) provide quick relief of nasal or ocular oedema. Therefore, they could improve the therapeutic effectiveness of topically applied antihistamines such as azelastine.
Formulations for the treatment of cold, cold-like and/or flu symptoms often contain antihistamines and decongestants. Until now, only oral combination preparations are on the market. The therapeutic activity of a non-sedating antihistamine, applied topically as for instance azelastine, a histamine Hi-receptor antagonist can effectively be supported by a-adrenergic agonists without increasing the risk of adverse effects.
Summary of the invention
It is therefore an object of the present invention to provide pharmaceutical combinations of matter, applicable topically, comprising an effective amount of a non-sedating antihistamine, preferably acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizine, epinastine, fexofenadine, loratidine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine in combination with an a-adrenergic agonist, preferably epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoline or xylometazoline and further optionally including pharmaceutically acceptable carriers and/or diluting agents or auxiliary substances therefor.

5
It is an additional object of the present invention to provide a method for the prophylaxis and treatment of allergic and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or flu symptoms in a mammalian organism in need of such treatment by topical administering a safe and effective amount of a combination comprising a non-sedating antihistamine, preferably acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizine, epinastine, fexofenadine, loratidine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine with an -adrenergic agonist, preferably epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoline or xylometazoline.
It is another object of the present invention to provide suitable dosage unit forms of a non-sedating antihistamine, preferably acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizine, epinastine, fexofenadine, loratidine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine in combination with an -adrenergic agonist, preferably epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazofine, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazoiine or xylometazoline, adapted for convenient topical administration, for instance, in the form of sprays or drops.
Detailed description of the invention
The antiallergic component in the pharmaceutical combination of the present invention includes a non-sedating antihistamine applied topically as for instance acrivastine, antazoline, astemizole, azelastine cetirizine, ebastine, efletirizine, epinastine, fexofenadine, loratidine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine or a pharmaceutically acceptable salt thereof. Azelastine is a histamine Hi-receptor antagonist of the second generation without sedating effect.
The concentration of the antihistaminic component of the present invention may range from 0.001% to 0.5%.

6
In addition to the antihistaminic component the pharmaceutical combinations of the
present invention comprise a topical decongestant, preferably epinephrine,
fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoline, phenylephrine,
tefazoline, tetryzoline, tramazoline, tymazoline or xylometazoline, or a
pharmaceutically acceptable salt thereof.
The concentration of a-adrenergic agonists in the combination may range from
0.001% to 0.2%.
The concentration of phenylephrine may however range from 0,01% to 15%, its
preferred concentration is between 0.1% to 2%.
The preferred concentrations are for the antihistaminic component 0.05% - 0.1% and for a-adrenergic agonists 0.05% - 0.1%, with exception of phenylephrine (its preferred concentration see above).
The active ingredients are administered topically as a mixture containing pharmaceutical diluents, excipients or carrier which are consistent with conventional pharmaceutical practices.
As representative suitable formulations consistent with the objects, features and advantages of the invention, the following examples are provided.
Dosages:
The pharmaceutical combination is administered as a rule, for nasal application :1 puff/nostril twice daily; maximum daily dose 3 puffs/nostril and for ocular application: 1 drop/eye twice daily, maximum daily dose 3-6 drops/eye.
The compositions for topical applications can be formulated in various
pharmaceutically acceptable forms e.g. as nasal sprays or nasal drops or as eye
drops.
Besides 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 buffer systems.

For example antimicrobial preservatives can include: benzalkonium chloride, chlorobutanol, thiomersal, methylparaben, propylparaben, sorbic acid, edetate disodium, phenylethanol, chlorhexidine HCI, chlorhexidine acetate, chlorhexidine digluconate, cetylpyhdinium chloride / bromide, chlorocresol, phenylmercuric acetate, phenylmercuric nitrate, phenylmercuric borate, phenoxyethanoi.
For preservation preferably a combination of edetate disodium and benzalkonium chloride is used. Edetate disodium is used in concentrations of 0.05 - 0.1 % and benzalkonium chloride in concentrations of 0.005 - 0.05 %.
Suitable excipients which can be used to adjust tonicity or osmolality 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 the viscosity and prolong contact of the drug with the tissue.
Such thickening agents may be: methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylates, polyacrylamide, dextran, gellan gum (Gelrite®), poloxamere, cellulose acetate phthalate.
The compositions of the present invention also include pharmaceutically acceptable buffers sufficient 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. These buffers can be built from substances like citric acid, monosodium phosphate, disodium phosphate, glycine, boric acid, sodium tetraborate, acetic acid, sodium acetate. Also other excipients can be used for pH-adjustment like hydrochloric acid or sodium hydroxide.
Further details of this invention are given by the following examples which should not be limitations to the scope of the present invention.

8
Example 1
Nasal spray or nasal drops containing Azelastine HCI (0.1%) and Oxymetazoline HC! (0.05%)
Example 2
Eye drops containing Azelastine HCI (0.05%) and Tetryzoline HCI (0.05%)
10 ml solution contain:

Example 3
Nasal spray or nasal drops
See example 1 but with 0.1 % Xylomethazoline HCI instead of 0.05%
Oxymethazoline HCI

9
Example 4
Eye drops
See example 2 but with 0.1% Naphazoline HCi instead of 0.05% Tetryzoline HCl
Example 5
Nasal spray or nasal drops
See example 1 but with 0.05% Naphazotine HCI instead of 0.05% Oxymethazoline
HCI
Example 6
Nasal spray or nasal drops
See example 1 but with 0.1264 % Tramazoline HCI instead of 0.05 %
Oxymethazoline HCI
Example 7
Eye drops
See example 2 but with 0.0632% Tramazoline HCI instead of 0.05% Tetryzoline HCI
Preparation of eye drops (Example 2, 4 and 7):
Prepare 45.0 kg of water for injections in a suitable container and dissolve therein
while stirring:

10
the active principles, edetate disodium, benzalkonium chloride, hydroxypropyi methylceilulose and sorbitol solution. Fill up the solution with water for injection to 49.5 litres. Adjust the pH of the solution with sodium hydroxyde solution 1N to pH 6. Fill up the solution with water for injections to get 50.0 litres and stir. Sterile-filter the solution through a membrane filter, pore size 0.2 urn. Fill the solution aseptically into sterilised bottles.
Preparation of nasal sprays or nasal drops (Example 1, 3, 5 and 6)
Prepare 96.5 kg of purified water in a suitable container and dissolve therein while
stirring:
the active principles, edetate disodium, sorbitoi solution, benzalkonium chloride,
disodium phosphate dodecahydrate, citric acid anhydrous and hydroxypropyi
methylcellulose. Fill up the solution to 100 litres and stir. Filter the solution through a
membrane filter of pore size 0.2 m and fill it into bottles.

-11-
WE CLAIM:
1. A pharmaceutical combination of matter for use in the treatment of allergic
and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or flu
symptoms, and adapted for unit dosage topical administration, said
combination comprising
a) 0.001% to 0.5% of a non-sedating antihistamine or a
pharmaceuticalfy acceptable salt thereof,
b) 0.001% to 0,2% of an -adrenergic agonist or a pharmaceutically
acceptable salt thereof with the exception of phenylephrine or
0.01 to 15% of phenylephrine;
c) conventional physiologically acceptable carriers and/or diluting
agents or auxiliary substances.
2. The pharmaceutical combination as claimed in claim 1, said non-sedating
antihistamines comprising acrivastine, antazoline, astemizole, azelastine,
cetirizing, ebastine , efletirizine, epinastine, fexofehadine, loratidine,
levocabastine, mizolastine, oxatomide, setastine, temelastine or
terfenadine.

-12-
3. The pharmaceutical combination as claimed In claim 1, said -adrenergic
agonists comprsing epinephrine, fenoxazopline, indanazoline,
naphazoiine, oxedrine, oxymetazoline, phenylephrine, tefazoline,
tetryzoline, tramazoline, tymazoline orxylometazoline.
4. The pharmaceutical combination as claimed in claims 1,2 and 4,
comprising preferably 0.05% to 0.1% of the antlhistamlnic component.
5. The pharmaceutical combination as claimed in claims 1,3 an 6, comprising
preferably 0.05% to 0.1% of -adrenergic agonist, with the exception of
phenylephrine.
6. The pharmaceutical combination as claimed in claims 1,3 and 8,
comprising preferably 0.1% to 2% of phenylephrine.
7. The pharmaceutical combination as claimed in claims 1 to 9 in topical
dosage form.
8. The pharmaceutical combination as claimed in claims 1 to 10 in topical
dosage spray form.
9. The pharmaceutical combination as claimed in claims 1 to 10 in topical
dosage drop form.

-13-
10. 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 -adrenerglc agoist or a pharmaceutically
acceptable salt thereof and
c) conventional physiologically acceptable carriers and/or diluting
agents or auxiliary substances.
For the production of a medicament for the prophylaxis and treatment of allergic and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or flu symptoms by topical administration.
11. A pharmaceutical combination of matter as defined by claim 13,
said non-sedating antihistamine comprising acrivastine, antazoline, astemizole, azelastine, cetirizine, ebastine, efletirizined, epinastine, fexofenadine, loratidine, levocabastine, mizolastine , oxatomide, setastine, lemelastine or terfenadine, for the production of a medicament for the prophylaxis and treatment of allergic and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or flu symptoms, by topical administration.

-14-
12. A pharmaceutical combination of matter as defined by claim 13,
said -adrenergic agonist comprising epinephrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymelazoline, phenylephrine, tefazoline, tetryzoline, tramazoline, tymazollne or xylometazoline for the production of a medicament for the prophylaxis and treatment of allergic and/or vasomotoric rhinrts, conjunctivitis, cold, cold-like and/or flu symptoms, by topical administration.
13, Medicaments for topical administration having action against allergic
and/or vasomotoric rhinitis, conjunctivitis, cold, cold-like and/or or flu
symptoms comprising
a) an effective amount of a non-sedating antihistamine or a
pharmaceutlcally acceptable salt thereof,
b) an effective amount of an a-adrenergic agonist or a
pharmaceutically acceptable salt thereof and
c) conventional physiologically acceptable carriers and/or diluting
agents or auxiliary substances.
17. Medicaments as claimed in claim 16, said non-sedating antihisfamine comprising acrivastine, antazoline, astemizole, azelastine, cetirrzine, ebastine, efletlrizine, eplnastine, fexofenadine, loratldine, levocabastine, mizolastine, oxatomide, setastine, temelastine or terfenadine.

¦15-
13. Medicaments as claimed In claim 16, said -adrenergic agonist comprising epineprtrine, fenoxazoline, indanazoline, naphazoline, oxedrine, oxymetazoitne, phenylephrine, tefazoline, tetryzoline, tramazoline tymazoline or xylometazoline.

Pharmaceutical combination, applicable topically, containing a non-sedating antihistamine in combination with an -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.

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Patent Number

209250

Indian Patent Application Number

01641/CAL/1998

PG Journal Number

34/2007

Publication Date

24-Aug-2007

Grant Date

23-Aug-2007

Date of Filing

14-Sep-1998

Name of Patentee

ASTA MEDICAL AKTIENGESELISCHAFT

Applicant Address

AN DER PIKARDIE 10, D-01277 DRESDEN, GERMANY

Inventors:

#	Inventor's Name	Inventor's Address
1	MARIA DEL CARMEN DIEZ CRESPO	AVENIDA MACHUPICHU NO 11, ESC. B 4OD, 28043 MADRID SPAIN
2	ISTVAN SZELENYL	HANDELSTRASSE 32, D-90571 SCHWAIG, GERMANY
3	REINHARD MUCKENSCHNABEL	AM WEISSEN TURM 33, D-60388, FRANKFURT, GERMANY
4	ROBERTO MAINARDI	RUA PADRE MARIANO FRIAS 67, 05101-070 SAO PAULO-SP, BRAZIL

PCT International Classification Number

A61 K45/06

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	97116494.2	1997-09-22	Germany