WO2013061269A1

WO2013061269A1 - Combinations of loteprednol and olopatadine for the treatment of ocular allergies

Info

Publication number: WO2013061269A1
Application number: PCT/IB2012/055874
Authority: WO
Inventors: Rajesh Kshirsagar; Shivanand Dhanure; Sachin Mundade
Original assignee: Micro Labs Limited
Priority date: 2011-10-26
Filing date: 2012-10-25
Publication date: 2013-05-02

Abstract

The present invention relates to use of a fixed dose combination comprising Loteprednol or its pharmaceutically acceptable esters/salts thereof and Olopatadine or its pharmaceutically acceptable salts thereof for the treatment of ocular allergy. The present invention further relates to a pharmaceutical composition comprising a fixed dose combination comprising Loteprednol or its pharmaceutically acceptable esters/salts thereof and Olopatadine or its pharmaceutically acceptable salts thereof for the treatment of ocular allergy.

Description

COMBINATIONS OF LOTEPREDNOL AND OLOPATADINE FOR THE TREATMENT OF OCULAR ALLERGIES

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 keratoconjunctivitis, 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, prostaglandins, leukotrienes and chemo attractants 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. However literature survey revealed that nobody till date has used fixed dose combination of Antiinflammatory steroids and histamine antagonists 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 the fixed dose combination of anti-inflammatory steroids and histamine antagonists is effective for 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 comprising one or more anti-inflammatory steroids and one or more histamine antagonists.

In one aspect, the present invention provides a fixed dose combination comprising one or more anti-inflammatory steroids and one or more histamine antagonists for the treatment of ocular allergy.

In yet another aspect, the present invention provides a pharmaceutical composition comprising fixed dose combination comprising one or more antiinflammatory steroids and one or more histamine antagonists 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 anti-inflammatory steroids and one or more histamine antagonists 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 of Loteprednol or its pharmaceutically acceptable esters/salts thereof and Olopatadine 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 Loteprednol or its pharmaceutically acceptable esters/salts thereof and Olopatadine or its pharmaceutically acceptable salts thereof for the treatment of ocular allergy. In another yet preferred aspect, the present invention provides a stable pharmaceutical composition comprising an effective amount of Loteprednol or its pharmaceutically acceptable esters/salts thereof, an effective amount of Olopatadine 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 Loteprednol Etabonate, Olopatadine Hydrochloride and pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF INVENTION

The invention includes the combinational use of one or more antiinflammatory steroids and one or more histamine antagonists for the treatment of ocular allergy. More specifically, the present invention includes the combinational use of Loteprednol or its pharmaceutically acceptable esters/salts thereof and Olopatadine or pharmaceutically acceptable salts thereof for the treatment 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 "anti-inflammatory steroids" refers to the drugs that block the synthesis of new histamine release by mast cells, inactivate available histamine, inhibit mast cell degranulation, decrease capillary permeability, and inhibit phospholipase A synthesis, which is used in the production of arachidonic acid and thereby prevent inflammation.

As used herein, the term "Histamine antagonists "refers to the drugs that counteract the action of histamine. The histamine antagonists therefore prevent the allergic reaction by acting on certain sub-types of histamine receptors such as HI histamine receptor, H2, H3 or H4 receptors and prevent the release of histamine which is responsible for allergic reaction upon exposure of allergen. Anti-inflammatory steroids like Loteprednol undergo a predictable transformation to its inactive metabolite upon reaching to its site of administration (intraocular or intranasal). As a result of this local metabolism, none or very little amount of drug reaches to systemic circulation and because of this steroid specific side effects are not observed.

Histamine antagonists are the fast-acting component and thus effective in elimination of the acute symptoms (e.g. reddening, itching, and swelling) occur during early phases of allergic reaction, while anti-inflammatory steroid provide better control of inflammation occur during allergic reaction. Thus the combination of histamine antagonist and anti-inflammatory steroid is much effective for treatment of ocular allergy.

In one embodiments, 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, suspension 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 either dissolved or suspended in the liquid medium (e.g., aqueous medium) based on their solubility in liquid medium.

In preferred embodiment, the present invention provides a combination of Anti-inflammatory steroids (preferably Loteprednol) and histamine antagonists (preferably Olopatadine) are administered topically (intranasally or intraocularly) as a fixed dose combination. As a result of this combination a quick onset of action occurs along with strong anti-inflammatory action.

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 Loteprednol or its pharmaceutically acceptable esters/salts thereof and Olopatadine or its pharmaceutically acceptable salts thereof.

In yet another embodiment, an anti-inflammatory steroids (e.g. Loteprednol Etabonate) are present in a composition or formulation described herein in an amount of about 0.01 to 1 wt%, more preferably 0.2 to 0.5 wt %.

In yet another embodiment, the histamine antagonists (e.g. Olopatadine Hydrochloride) are present in a composition or formulation described herein in an amount of about 0.01 to 1 wt%, more preferably 0.1 to 0.3 wt %.

In yet other embodiment, an ophthalmic composition of present invention have a pH from 4.0 to 8.0, preferably from 4.5 to 7.5, more preferably from 5.2 to 7.2.

In yet another embodiment, an ophthalmic composition of present invention has an osmolarity from 200 to 400 milliosmoles/liter (mOsm/L), preferably from 250 to 375 mOsm/L, and more preferably from 300 to 360 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 anti-inflammatory steroids according to the present invention include, but are not limited to, Loteprednol etabonate, Prednisolone sulfacetamide, Hydrocortisone , Difluprednate, Fluorometholone acetate, Dexamethasone, Prednisolone phosphate , Rimexolone, 21 -acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, diflorasone, diflucortolone, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortarnate, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, prednisone, methylprednisolone, medrysone, triamcinolone or its physiologically acceptable salts thereof, prodrugs thereof, combinations thereof, mixtures thereof and the like.

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 physiologically acceptable salts thereof, prodrugs thereof, combinations thereof, mixtures thereof and the like.

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, wetting agents.

Examples of buffering agents include, but are not limited to, phosphate buffer such as Disodium hydrogen phosphate heptahydrate, Sodium dihydrogen phosphate monohydrate, borate buffer such as sodium borate, boric acid, citrate buffer, acetate buffer, carbonate buffer, borate-polyol complexes 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 salts, thimerosal, chlorobutanol, other quaternary amines and the like, chlorhexidine gluconate and the like. Examples of tonicity-adjusting agents include, but are not limited to, glycerin, 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 (NaHCOs) 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 (Povidone), polyethylene glycol, polyvinyl acetate, and combinations thereof.

Examples of wetting agents include, but are not limited to cetylpyridinium chloride, tyloxapol, various polysorbates such as Tween^®' polyethoxylated substances and poloxamers.

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.l: Ophthalmic Suspension containing Loteprednol Etabonate (0.2% w/v suspended) and Olopatadine Hydrochloride Eq. to Olopatadine base (0.1% w/v dissolved)

Sr. No. Name of Pharmaceutical Ingredient Quantity (mg/mL)

1 Loteprednol Etabonate 2.0

2 Olopatadine Hydrochloride 1.1 1

3 Benzalkonium Chloride 0.1

4 Disodium Edetate 0.1 5 Disodium hydrogen phosphate heptahydrate 0.47

6 Sodium Dihydrogen phosphate Monohydrate 1.13

7 Povidone 6.0

8 Tyloxapol 3.0

9 Glycerin 24.0

10 Sodium Hydroxide/Hydrochloric acid q.s

11 Water for injections q.s to 1 mL

Manufacturing process:

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

(a) Required quantity of Glycerin, Disodium Edetate, Disodium hydrogen phosphate

Heptahydrate, Sodium Dihydrogen phosphate monohydrate, Tyloxapol were introduced into suitable container and dissolved in sufficient water for injection and stirred until clear colorless solution was obtained.

(b) Accurately weighed quantity of Olopatadine hydrochloride was dissolved in solution of step (a) and stirred till clear solution was obtained.

(c) Required quantity of povidone was dissolved in sufficient quantity of water for injection in separate container and stirred till clear solution was obtained; this solution was added to solution of step (a) with stirring.

(d) Required quantity of Benzalkonium chloride was dissolved in sufficient quantity of water for injection in separate container and stirred till clear solution was obtained; this solution was added to solution of step (a) with stirring to obtain a final solution. (e) The pH of final solution obtained as per step (d) was adjusted to 6.2 with required quantity of IN NaOH or 0.1N HCL stock solution and final volume of desired batch size was made up with sufficient quantity of water for injection.

(f) The final solution of step (e) was then filtered through 0.22 μ filter.

(g) Accurately weighed quantity of Loteprednol Etabonate (micronized and sterilized) was added to filtered solution of step (f) under laminar air flow unit and homogenized to obtain a final sterile suspension. 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 Suspension containing Loteprednol Etabonate (0.5% w/v suspended) and Olopatadine Hydrochloride Eq. to Olopatadine base (0.2% w/v dissolved)

Manufacturing process:

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

(a) Required quantity of Glycerin, Disodium Edetate, Disodium hydrogen phosphate Heptahydrate, Sodium Dihydrogen phosphate monohydrate, Tyloxapol were introduced into suitable container and dissolved in sufficient water for injection and stirred until clear colorless solution was obtained.

(b) Accurately weighed quantity of Olopatadine hydrochloride was dissolved in solution of step (a) and stirred till clear solution was obtained. (c) Required quantity of povidone was dissolved in sufficient quantity of water for injection in separate container and stirred till clear solution was obtained; this solution was added to solution of step (a) with stirring.

(d) Required quantity of Benzalkonium chloride was dissolved in sufficient quantity 5 of water for injection in separate container and stirred the mixture till clear solution was obtained; this solution was added to solution of step (a) with stirring to obtain a final solution.

(e) The pH of final solution obtained as per step (d) was adjusted to 6.2 with required quantity of IN NaOH or 0.1N HCL stock solution and final volume of desired batch

10 size was made up with sufficient quantity of water for injection.

(f) The final solution of step (e) was then filtered through 0.22 μ filter.

(g) Accurately weighed quantity of Loteprednol Etabonate (micronized and sterilized) was added to filtered solution of step (f) under laminar air flow unit and homogenized to obtain a final sterile suspension.

15 The formulation of example 2 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. 4.

Table No.3: Loteprednol Etabonate and Olopatadine Hydrochloride Eq. to 20 Olopatadine base Ophthalmic Suspension (0.2 % w/v and 0.1 % w/v) finished product analysis data - initial and on stability

Preservative content NLT60.0% & 103.7 103.3 106.5 105.5 103.3 104.6 in % NMT120.0%

pH 5.2 to 7.2 6.28 6.17 6.08 5.60 6.26 6.23

Osmolality (mOsml/kg) 300 to 360 332 313 322 332 315 331

Table No. 4: Loteprednol Etabonate and Olopatadine Hydrochloride Eq. to Olopatadine base Ophthalmic Suspension (0.5 % w/v and 0.2 % w/v) finished product analysis data-initial and on stability

5

10

15

Claims

We claim:

1. A stable pharmaceutical composition comprising an effective amount of Loteprednol or its pharmaceutically acceptable esters/salts thereof, an effective amount of Olopatadine or its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

2. The composition of claim 1, wherein the composition comprises from about 0.01 to about 1 % (w/v) of Loteprednol Etabonate.

3. The composition of claim 1, wherein the composition comprises from about 0.01 to about 1 % (w/v) of Olopatadine hydrochloride.

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

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

6. The pharmaceutical composition of claim 1, wherein the composition has a pH in the range from 5.2 to 7.2.

7. The pharmaceutical composition of claim 1, wherein the composition has an Osmolality in the range from 300 to 360 mOsml/kg.

8. A process for preparation of a pharmaceutical composition comprising the steps of: (a) admixing an Olopatadine hydrochloride and pharmaceutically acceptable excipients to form a mixture; (b) adjusting a pH of said mixture in the range of 5.2 to 7.2 with pH-adjusting agents and (c) filtering the mixture and (d) adding the Loteprednol Etabonate to the filtered mixture followed by homogenization to obtain a sterile suspension.

9. A method of treating an ocular allergy, comprising administering to an affected eye of patient a combination of effective amount of Loteprednol or its pharmaceutically acceptable esters/salts thereof and Olopatadine 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.