WO2013061269A1 - Associations de loteprednol et d'olopatadine destinées au traitement de l'allergie oculaire - Google Patents

Associations de loteprednol et d'olopatadine destinées au traitement de l'allergie oculaire Download PDF

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Publication number
WO2013061269A1
WO2013061269A1 PCT/IB2012/055874 IB2012055874W WO2013061269A1 WO 2013061269 A1 WO2013061269 A1 WO 2013061269A1 IB 2012055874 W IB2012055874 W IB 2012055874W WO 2013061269 A1 WO2013061269 A1 WO 2013061269A1
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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
composition
olopatadine
loteprednol
salts
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PCT/IB2012/055874
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English (en)
Inventor
Rajesh Kshirsagar
Shivanand Dhanure
Sachin Mundade
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Micro Labs Limited
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Publication of WO2013061269A1 publication Critical patent/WO2013061269A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics

Definitions

  • 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.
  • the eye particularly the conjunctiva, has a relatively large number of mast cells.
  • allergens 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.
  • the acute phase response can progress to a late phase response characterized by an influx of eosinophils and neutrophils into the conjunctiva.
  • a late phase response characterized by an influx of eosinophils and neutrophils into the conjunctiva.
  • vernal keratoconjunctivitis exemplified by vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis
  • eyelid swelling and remodeling of the ocular surface tissues can occur.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a process for preparation of a pharmaceutical composition comprising Loteprednol Etabonate, Olopatadine Hydrochloride and pharmaceutically acceptable excipients.
  • 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.
  • 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.
  • SAC Seasonal Allergic Conjunctivitis
  • PAC Perennial Allergic Conjunctivitis
  • Vernal Keratoconjunctivitis Vernal Keratoconjunctivitis
  • Atopic Keratoconjunctivitis Atopic Keratoconjunctivitis.
  • 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.
  • Histamine antagonists refer 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.
  • 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.).
  • 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.
  • liquid medium e.g., aqueous medium
  • 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.
  • Anti-inflammatory steroids preferably Loteprednol
  • histamine antagonists preferably Olopatadine
  • 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.
  • 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.
  • an anti-inflammatory steroids e.g. Loteprednol Etabonate
  • an anti-inflammatory steroids 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 %.
  • the histamine antagonists e.g. Olopatadine Hydrochloride
  • the histamine antagonists 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 %.
  • 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.
  • 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.
  • mOsm/L milliosmoles/liter
  • 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.
  • anti-inflammatory steroids examples 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,
  • histamine antagonists 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, warmthlastine, trimeprazine, triprolidine, bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyprohept
  • 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.
  • 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.
  • 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.
  • tonicity-adjusting agents include, but are not limited to, glycerin, mannitol, sodium chloride, xylitol, and the like.
  • alkaline agents examples include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, monoethanolamine, sodium bicarbonate (NaHCOs) and other organic and inorganic bases.
  • NaOH sodium hydroxide
  • KOH potassium hydroxide
  • tromethamine monoethanolamine
  • NaHCOs sodium bicarbonate
  • acidic agents examples 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.
  • chelating agents include, but are not limited to, EDTA, disodium edetate, sodium citrate, condensed sodium phosphate and the like
  • viscosity modifiers include, but are not limited to, hydroxypropylmethyl cellulose (hypromellose), carboxypropylmethylcellulose, polyvinylpyrrolidone (Povidone), polyethylene glycol, polyvinyl acetate, and combinations thereof.
  • wetting agents include, but are not limited to cetylpyridinium chloride, tyloxapol, various polysorbates such as Tween ® ' polyethoxylated substances and poloxamers.
  • a formulation as shown in table 1 was prepared as follows:
  • 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.
  • step (b) Accurately weighed quantity of Olopatadine hydrochloride was dissolved in solution of step (a) and stirred till clear solution was obtained.
  • step (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.
  • step (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.
  • step (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.
  • step (f) The final solution of step (e) was then filtered through 0.22 ⁇ filter.
  • step (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.
  • a formulation as shown in table 2 was prepared as follows:
  • step (b) Accurately weighed quantity of Olopatadine hydrochloride was dissolved in solution of step (a) and stirred till clear solution was obtained.
  • step (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.
  • step (f) The final solution of step (e) was then filtered through 0.22 ⁇ filter.
  • step (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.
  • 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
  • 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

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Abstract

L'invention concerne l'utilisation, pour le traitement de l'allergie oculaire, d'une association à dose fixe comprenant du Loteprednol ou des esters/sels pharmaceutiquement acceptables de ce dernier et de l'Olopatadine ou des sels pharmaceutiquement acceptables de celle-ci. L'invention se rapporte aussi à une composition pharmaceutique destinée au traitement de l'allergie oculaire, qui comprend une association à dose fixe de Loteprednol ou d'esters/sels pharmaceutiquement acceptables de ce dernier et d'Olopatadine ou de sels pharmaceutiquement acceptables de celle-ci.
PCT/IB2012/055874 2011-10-26 2012-10-25 Associations de loteprednol et d'olopatadine destinées au traitement de l'allergie oculaire WO2013061269A1 (fr)

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US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
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US11713323B2 (en) 2013-11-01 2023-08-01 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11021487B2 (en) 2016-09-08 2021-06-01 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11104685B2 (en) 2016-09-08 2021-08-31 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10766907B2 (en) 2016-09-08 2020-09-08 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10253036B2 (en) 2016-09-08 2019-04-09 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10626121B2 (en) 2016-09-08 2020-04-21 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10336767B2 (en) 2016-09-08 2019-07-02 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof

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