FIELD OF THE INVENTION:

The present invention is directed to methods and compositions for the treatment of ocular allergy, including seasonal and perennial allergic conjunctivitis, vernal kera to conjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis.

BACKGROUND OF THE INVENTION

The eye, particularly the conjunctiva, has a relatively large number of mast cells. When allergens are present they can bind to immunoglobulins on the surface of these mast cells and trigger their degranulation (breakdown). Degranulation releases mast cell components, including histamine, into the environment outside the mast cell. Through a variety of mechanisms these components produce ocular surface inflammation resulting in itching, tearing, lid and conjunctival edema/redness, and photophobia. This is frequently designated as an acute phase response, as is seen with seasonal allergic conjunctivitis and perennial allergic conjunctivitis. As is the case in other allergic diseases, the acute phase response can progress to a late phase response characterized by an influx of eosinophils and neutrophils into the conjunctiva. In the associated chronic allergic disease, exemplified by vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis, eyelid swelling and remodeling of the ocular surface tissues can occur. In severe cases the patient experiences extreme discomfort and sustains damage to the ocular surface. For such instances there is no highly effective and safe treatment regimen. Although topical administration of corticosteroids is effective in severe cases, chronic use is contraindicated due to an increased risk for the development of cataracts and glaucoma. In the treatment of ocular allergic conditions the treatment of choice is either use of histamine antagonists or one mast cell stabilizers. However literature survey revealed that no body till date has used fixed dose combination of histamine antagonists and mast cell stabilizers for the treatment of ocular allergic disorders, such as allergic conjunctivitis, giant papillary conjunctivitis, vernal conjunctivitis, and atopic keratoconjunctivitis.

Thus there is unmet need in the art to provide an effective treatment of ocular allergic disorders such as allergic conjunctivitis, giant papillary conjunctivitis, vernal conjunctivitis, and atopic keratoconjunctivitis. The present inventors have found that fixed dose combination of histamine antagonists and mast cell stabilizers for effective treatment of ocular allergic disorders such as allergic conjunctivitis, giant papillary conjunctivitis, vernal conjunctivitis, and atopic keratoconjunctivitis.

SUMMARY OF THE INVENTION

The present invention is directed to a method of treating ocular allergy, including seasonal and perennial allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis in a patient suffering from or predisposed thereto, comprising administration of a fixed dose combination of one or more histamine antagonists and one or more mast cell stabilizers.

In one aspect, the present invention provides a fixed dose combination of one or more histamine antagonists and one or more mast cell stabilizers for the treatment of ocular allergy.

In yet another aspect, the present invention provides a pharmaceutical composition comprising fixed dose combination of one or more histamine antagonists and one or more mast cell stabilizers for the treatment of ocular allergy.

In yet another aspect, the present invention provides a process for preparation of a pharmaceutical composition comprising fixed dose combination of one or more histamine antagonists and one or more mast cell stabilizers for the treatment of ocular allergy.

In yet preferred aspect, the present invention provides a method of treating an ocular allergy, comprising administering to an affected eye of patient a combination of effective amount Azelastine or its pharmaceutically acceptable salts thereof and Cromolyn or its pharmaceutically acceptable salts thereof optionally together with pharmaceutically acceptable excipients.

In yet another preferred aspect, the present invention provides a fixed dose combination of Azelastine or its pharmaceutically acceptable salts thereof and Cromolyn or its pharmaceutically acceptable salts thereof for the treatment of ocular allergy.

In yet another preferred aspect, the present invention provides a stable pharmaceutical composition comprising an effective amount of Azelastine or its pharmaceutically acceptable salts thereof, an effective amount of Cromolyn or its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

In yet another preferred aspect, the present invention provides a process for preparation of a pharmaceutical composition comprising Azelastine hydrochloride, Cromolyn sodium and pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF INVENTION

The invention includes the combinational use of one or more histamine antagonists and one or more mast cell stabilizers for the treatment and prevention of ocular allergy. More specifically present invention includes the combinational use of Azelastine or its pharmaceutically acceptable salts thereof and Cromolyn or its pharmaceutically acceptable salts thereof for the treatment and prevention of ocular allergy.

As used herein, the term "ocular allergy" refers to an allergic disorder of the ocular surface caused by pathogenic allergens. Allergic conjunctivitis is the preferred ocular allergy and includes a wide variety of pathological conditions including Seasonal Allergic Conjunctivitis ("SAC"), Perennial Allergic Conjunctivitis ("PAC"), Vernal Keratoconjunctivitis and Atopic Keratoconjunctivitis. Mast cells are primarily responsible for the hypersensitivity reaction that occurs in SAC and PAC.

As used herein, the term "Histamine antagonists" refers to the drugs that counteract the action of histamine. Histamine antagonists therefore prevent the allergic reaction by acting on certain sub-types of histamine receptors such as H1 histamine receptor, H2, H3 or H4 receptors and prevent the release of histamine which is responsible for allergic reaction upon exposure of allergen.

As used herein, the term "mast cell stabilizers" refers to the drugs that inhibit mast cell degranulation, thereby reducing the release of inflammatory substances.

Allergic reactions generally arise from prior exposure to an allergen, resulting in sensitization. Upon re-exposure, allergen-specific IgE antibodies bind to receptor sites in mast cells. This causes a release of chemical mediators from the mast cells and mast cell degranulation. While there are a number of agents released from the mast cells, histamine plays a major role in the "immediate allergic response," resulting in increased vascular permeability, chemosis and redness.

With degranulation there is some degree of accompanying inflammatory response, with IgE cross-linking leading other mediators to recruit cells for a "late allergic response," some six to twelve hours later.

Histamine antagonists are the fast-acting component and the mast cell stabilizers are slower acting but prevent the allergic cascade from occurring. So it is advantageous to provide combination of histamine antagonist-mast cell stabilizer to get rapid therapeutic onset, and they can be safely used over an extended period of time.

Histamine antagonists are employed in the acute phase of allergic reaction for the alleviation of the often irritating symptoms. The topical application of these medicaments is particularly advantageous, as high local concentrations of the active compound can be broken down in this way without having to reckon with appreciable side effect.

Thus the combination of present invention provides rapid elimination of the acute symptoms (e.g. reddening, itching, and swelling) and control of chronic symptoms of allergic reaction.

More preferably the combination of present invention can be used mild to moderate allergic reaction like seasonal allergic conjunctivitis as well as chronic allergic reaction like allergic conjunctivitis, such as vernal or atopic Keratoconjunctivitis.

The various embodiments of the present invention can be assembled in several different ways.

In one embodiment, compositions and formulations described herein comprise a first active agent and a second active agent, wherein the first active agent and the second active agent are formulated into the composition or formulation in a manner that allows ophthalmic and/or topical activity of the agents (e.g., by formulating a composition or formulation described herein as a solution, gel, or the like, comprising a first active agent and a second active agent as solutes within the solution, gel, etc.). It is to be understood that such compositions and formulations include compositions and formulations wherein a substantial portion, a therapeutically effective portion, most or all of the first and second agents are dissolved in the liquid medium (e.g., aqueous medium).

In one advantageous embodiment, the active components of present invention are present in the form of a fixed dose combination, owing to which the administration is simpler for the patients, since both active compounds are contained in one and the same container.

In specific embodiment, the present invention provides a fixed dose combination of Azelastine or its pharmaceutically acceptable salts thereof and Cromolyn or its pharmaceutically acceptable salts thereof.

In yet another embodiment, the histamine antagonist (e.g. Azelastine hydrochloride) is present in a composition or formulation described herein in an amount of about 0.01 to about 0.1 wt%, more preferably 0.05 wt %.

In yet another embodiment, the mast cell stabilizer (e.g. Cromolyn sodium) is present in the composition or formulation described herein in an amount of about 1 to about 10 wt %, more preferably 2 to 4 wt%.

In yet other embodiment, an ophthalmic composition of present invention have a pH from 4.0 to 8.0, preferably from 5 to 7, more preferably from 5.5 to 6.5.

In yet another embodiment, an ophthalmic composition of present invention have an osmolality from 200 to 400 milliosmoles/liter (mOsm/L), preferably from 250 to 350 mOsm/L, and more preferably from 270 to 330 mOsm/L.

In yet another embodiment, the compositions, formulations and active pharmaceutical agent described herein are thermally stable at room temperature, at 25 °C with relative humidity 40% or at 40 °C with relative humidity NMT 25% for at least 3 months.

Examples of histamine antagonists according to the present invention include, but are not limited to, azelastine, acrivastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, ketotifen, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast, tripelenamine, temelastine, trimeprazine, triprolidine, bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, astemizole, terfenadine, loratadine, cetirizine, levocetirizine, fexofenadine, descarboethoxyloratadine, desloratadine, dimenhydrinate, hydroxyzine, thioperamide, impromidine, burimamide, clobenpropit, impentamine, mifetidine, clozapine, S-sopromidine, R-sopromidine, ciproxifam or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, pro-drugs, or mixtures thereof.

Examples of mast cell stabilizers according to the present invention include, but are not limited to cromolyn sodium, nedcromil sodium, pemirolast, lodoxamise trometamol, odoxamide, and sodium cromoglycate or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, pro-drugs, or mixtures thereof.

A pharmaceutical composition according to the present invention may include one or more pharmaceutically acceptable buffering agents, preservatives, tonicity-adjusting agents, pH-adjusting agents, chelating agents, viscosity modifier.

Examples of buffering agents include, but are not limited to, phosphate buffer, borate buffer, citrate buffer, acetate buffer, carbonate buffer, borate-polyol complexes, boric acid and the like.

Examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, p- oxybenzoates such as methyl p-oxybenzoate or ethyl p-oxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid or its salt, thimerosal, chlorobutanol, other quaternary amines and the like, chlorhexidine gluconate and the like.

Examples of tonicity-adjusting agents include, but are not limited to, sorbitol, mannitol, sodium chloride, xylitol, and the like.

Examples of the alkaline agents that may be used as pH adjusting agents include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, monoethanolamine, sodium bicarbonate (NaHC03) and other organic and inorganic bases.
Examples of the acidic agents that may be used as pH adjusting agents include, but are not limited to, hydrochloric acid, citric acid, tartaric acid, lactic acid and other organic and inorganic acids and the like and mixtures thereof.

Examples of chelating agents include, but are not limited to, EDTA, disodium Edetate, sodium citrate, condensed sodium phosphate and the like

Examples of viscosity modifiers include, but are not limited to, hydroxypropylmethyl cellulose (hypromellose), carboxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl acetate, and combinations thereof.

Examples

The invention will be further illustrated by the following examples, which are intended to be illustrative but not limiting.

Example No. 1

Table No. 1 Ophthalmic Solution containing Azelastine Hydrochloride (0.05% w/v) and Cromolyn Sodium (4 % w/v)

Manufacturing process:

A formulation as shown in table 1 was prepared as follows:

(a) Accurately weighed quantity of Azelastine Hydrochloride, Cromolyn Sodium,
Disodium Edetate and sorbitol were dissolved in a sufficient quantity of water for injection in suitable container and stirred until clear colorless solution was obtained.
(b) Required quantity of hypromellose was dissolved in a sufficient quantity of water for injection in separate container and stirred until clear solution obtained and resultant solution was added to solution of step (a) with stirring.
(c) Required quantity of Benzalkonium chloride was dissolved in sufficient quantity of water for injection in separate container and stirred until clear solution obtained and resultant solution was added to a solution of step (a) to obtain a final solution.
(d) The pH of final solution obtained as per step (c) was adjusted to 6.0 by addition of required quantity of 1 N sodium hydroxide solution or 0.1 N hydrochloric acid solution and final volume of desired batch size was made-up using a sufficient quantity of water for injection.
(e) The final solution from step (d) was filtered through 0.22u filter to obtain a final sterile formulation.

The formulation of example 1 was further subjected to stability studies at 40°C/NMT25%RH, was analyzed at an intervals of 1M, 2M & 3M and at 25°C/40%RH, was analyzed at an intervals of 1M and 3M, the results obtained are presented in Table No. 3.

Example No. 2

Table No. 2 Ophthalmic Solution containing Azelastine Hydrochloride (0.05% w/v) and Cromolyn Sodium (2 % w/v)

Manufacturing process:

A formulation as shown in table 2 was prepared as follows:

(a) Accurately weighed quantity of Azelastine Hydrochloride, Cromolyn Sodium,
Disodium Edetate and sorbitol were dissolved in a sufficient quantity of water for
injection in suitable container and stirred until clear colorless solution was obtained.
(b) Required quantity of hypromellose was dissolved in a sufficient quantity of water for injection in separate container and stirred until clear solution obtained and resultant solution was added to solution of step (a) with stirring.
(c) Required quantity of Benzalkonium chloride was dissolved in sufficient quantity of water for injection in separate container and stirred until clear solution obtained and resultant solution was added to a solution of step (a) to obtain a final solution.
(d) The pH of final solution obtained as per step (c) was adjusted to 6.0 by addition of required quantity of 1 N sodium hydroxide solution or 0.1 N hydrochloric acid solution and final volume of desired batch size was made-up using a sufficient quantity of water for injection.
(e) The final solution from step (d) was filtered through 0.22u filter to obtain a final sterile formulation.

The formulation of example 2 was further subjected to stability studies at 40°C/NMT25%RH, was analyzed at an intervals of 1M & 2M and at 25°C/40%RH, was analyzed at an intervals of 1M , the results obtained are presented in Table No.4.

Table No. 3 Azelastine hydrochloride and Cromolyn sodium ophthalmic Solution (0.05% w/v and 4.0% w/v) finished product analysis data-initial and on stability

We claim:

1. A stable pharmaceutical composition comprising an effective amount of Azelastine or its pharmaceutical^ acceptable salts thereof, an effective amount of Cromolyn or its pharmaceutical^ acceptable salts thereof and pharmaceutical^ acceptable excipients.
2. The composition of claim 1, wherein the composition comprises from about 0.01 to about 0.1 % (w/v) of Azelastine hydrochloride.

3. The composition of claim 1, wherein the composition comprises from about 1 to about 10 % (w/v) of Cromolyn sodium.

4. The composition of claim 1, wherein said composition is intended for ocular use.

5. The composition of claim 1, wherein the pharmaceutical acceptable excipients are selected from the group consisting of buffering agents, preservatives, tonicity-adjusting agents, pH-adjusting agents, chelating agents, viscosity modifiers and combination thereof.

6. The pharmaceutical composition of claim 1, wherein the composition has a pH in the range from 5.5 to 6.5.

7. The pharmaceutical composition of claim 1, wherein the composition has an Osmolality in the range from 270 to 330 mOsml/kg.

8. A process for preparation of a pharmaceutical composition comprising the steps of: (a) admixing Azelastine or its pharmaceutically acceptable salts thereof and Cromolyn or its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients to form a mixture; (b) adjusting a pH of said mixture in the range of 5.5 to 6.5 with pH-adjusting agents and (c) filtering the mixture to obtain a final sterile composition.

9. A method of treating an ocular allergy comprising administering to an affected eye of patient, a combination of effective amount of Azelastine or its pharmaceutically acceptable salts thereof and Cromolyn or its pharmaceutically acceptable salts thereof optionally together with pharmaceutically acceptable excipients.

10. The method of claim 9, wherein said ocular allergy is seasonal Allergic Conjunctivitis , Perennial Allergic Conjunctivitis, Vernal Keratoconjunctivitis and atopic Keratoconjunctivitis or combination thereof.