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WO2013068876A1 - Procédés et compositions pour traiter une allergie oculaire - Google Patents

Procédés et compositions pour traiter une allergie oculaire Download PDF

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Publication number
WO2013068876A1
WO2013068876A1 PCT/IB2012/055958 IB2012055958W WO2013068876A1 WO 2013068876 A1 WO2013068876 A1 WO 2013068876A1 IB 2012055958 W IB2012055958 W IB 2012055958W WO 2013068876 A1 WO2013068876 A1 WO 2013068876A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
composition
acceptable salts
azelastine
cromolyn
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2012/055958
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English (en)
Inventor
Rajesh Kshirsagar
Shivanand Dhanure
Sachin Mundade
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Micro Labs Ltd
Original Assignee
Micro Labs Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Micro Labs Ltd filed Critical Micro Labs Ltd
Publication of WO2013068876A1 publication Critical patent/WO2013068876A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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, 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 chronic allergic disease exemplified by vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis
  • eyelid swelling and remodeling of the ocular surface tissues can occur.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a process for preparation of a pharmaceutical composition comprising Azelastine hydrochloride, Cromolyn sodium and pharmaceutically acceptable excipients.
  • 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.
  • 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.
  • 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 HI histamine receptor, H2, H3 or H4 receptors and prevent the release of histamine which is responsible for allergic reaction upon exposure of allergen.
  • 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.
  • 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.
  • acute symptoms e.g. reddening, itching, and swelling
  • 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.
  • 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.).
  • 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).
  • 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 Azelastine or its pharmaceutically acceptable salts thereof and Cromolyn or its pharmaceutically acceptable salts thereof.
  • the histamine antagonist e.g. Azelastine hydrochloride
  • the histamine antagonist 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 %.
  • the mast cell stabilizer e.g. Cromolyn sodium
  • the mast cell stabilizer 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%.
  • 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.
  • 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.
  • 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.
  • 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
  • mast cell stabilizers 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.
  • 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.
  • 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.
  • tonicity-adjusting agents include, but are not limited to, sorbitol, 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 (NaHC0 3 ) and other organic and inorganic bases.
  • 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, polyethylene glycol, polyvinyl acetate, and combinations thereof.
  • a formulation as shown in table 1 was prepared as follows:
  • step (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.
  • step (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.
  • step (e) The final solution from step (d) was filtered through 0.22 ⁇ filter to obtain a final sterile formulation.
  • 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) 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.
  • step (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.
  • step (e) The final solution from step (d) was filtered through 0.22 ⁇ filter to obtain a final sterile formulation.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation d'une combinaison à dose fixe comprenant de l'azélastine ou ses sels pharmaceutiquement acceptables et de l'acide cromoglicique ou ses sels pharmaceutiquement acceptables pour le traitement d'une allergie oculaire. La présente invention concerne en outre une composition pharmaceutique comprenant une combinaison à dose fixe comprenant de l'azélastine ou ses sels pharmaceutiquement acceptables et de l'acide cromoglicique ou ses sels pharmaceutiquement acceptables pour le traitement d'une allergie oculaire.
PCT/IB2012/055958 2011-11-08 2012-10-29 Procédés et compositions pour traiter une allergie oculaire Ceased WO2013068876A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2332/CHE/2011 2011-11-08
IN2332CH2011 2011-11-08

Publications (1)

Publication Number Publication Date
WO2013068876A1 true WO2013068876A1 (fr) 2013-05-16

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PCT/IB2012/055958 Ceased WO2013068876A1 (fr) 2011-11-08 2012-10-29 Procédés et compositions pour traiter une allergie oculaire

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8937178B2 (en) 2013-03-13 2015-01-20 Flatley Discovery Lab Phthalazinone compounds and methods for the treatment of cystic fibrosis

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0433766A1 (fr) * 1989-12-18 1991-06-26 Alcon Laboratories, Inc. Composition d'anti-allergiques et d'anti-histaminiques et procédé pour leur application
WO1997001340A1 (fr) * 1995-06-29 1997-01-16 Mcneil-Ppc, Inc. Combinaison d'antihistamines nasales topiques et de stabilisateurs de mastocytes topiques par voie nasale
WO2005030331A1 (fr) * 2003-09-26 2005-04-07 Fairfield Clinical Trials, Llc Traitement antihistaminique combine
US7687539B1 (en) * 2005-11-07 2010-03-30 Alcon Research, Ltd. Method of treating ocular allergy

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0433766A1 (fr) * 1989-12-18 1991-06-26 Alcon Laboratories, Inc. Composition d'anti-allergiques et d'anti-histaminiques et procédé pour leur application
WO1997001340A1 (fr) * 1995-06-29 1997-01-16 Mcneil-Ppc, Inc. Combinaison d'antihistamines nasales topiques et de stabilisateurs de mastocytes topiques par voie nasale
WO2005030331A1 (fr) * 2003-09-26 2005-04-07 Fairfield Clinical Trials, Llc Traitement antihistaminique combine
US7687539B1 (en) * 2005-11-07 2010-03-30 Alcon Research, Ltd. Method of treating ocular allergy

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8937178B2 (en) 2013-03-13 2015-01-20 Flatley Discovery Lab Phthalazinone compounds and methods for the treatment of cystic fibrosis
US9783529B2 (en) 2013-03-13 2017-10-10 Flatley Discovery Lab, Llc Pyridazinone compounds and methods for the treatment of cystic fibrosis
US9790215B2 (en) 2013-03-13 2017-10-17 Flatley Discovery Lab, Llc Pyridazinone compounds and methods for the treatment of cystic fibrosis

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