EP3843721A1 - Ophthalmische zusammensetzungen und verfahren zur verwendung - Google Patents

Ophthalmische zusammensetzungen und verfahren zur verwendung

Info

Publication number
EP3843721A1
EP3843721A1 EP19856338.9A EP19856338A EP3843721A1 EP 3843721 A1 EP3843721 A1 EP 3843721A1 EP 19856338 A EP19856338 A EP 19856338A EP 3843721 A1 EP3843721 A1 EP 3843721A1
Authority
EP
European Patent Office
Prior art keywords
combination
ophthalmic
nanoemulsion
formulation
group
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.)
Withdrawn
Application number
EP19856338.9A
Other languages
English (en)
French (fr)
Other versions
EP3843721A4 (de
Inventor
Rasappa Arumugham
Arun UPADHYAY
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.)
Ocugen Inc
Original Assignee
Ocugen Inc
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
Priority claimed from US16/116,872 external-priority patent/US20190008920A1/en
Application filed by Ocugen Inc filed Critical Ocugen Inc
Publication of EP3843721A1 publication Critical patent/EP3843721A1/de
Publication of EP3843721A4 publication Critical patent/EP3843721A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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

Definitions

  • the present invention relates to an ophthalmic composition
  • an ophthalmic composition comprising at least two active pharmaceutical ingredients.
  • the active pharmaceutical ingredients are selected from the group consisting of: an alpha 2 adrenergic receptor agonist; a beta-adrenergic receptor agonist; an immunosuppressant; a lymphocyte associated antigen antagonist; an anti inflammatory; a beta-blocker; a prostaglandin analog; a histamine receptor antagonist; a carbonic anhydrase inhibitor; and an antibiotic.
  • the composition of the invention is a nanoemulsion formulation.
  • the present invention also provides a method for treating various clinical conditions associated with an eye disorder or eye disease using the composition of the invention.
  • Dry eye syndrome is a multifactorial disease. Dry eye syndromes engender inflammation and ocular surface irritation. Thus, the goals for the treatment of dry eye syndrome are to improve the patient's ocular comfort and to return the ocular surface and tear composition to their basal and healthy states.
  • Conventional treatments for dry eye syndrome include (i) instillation of artificial tears for tear supplementation and stimulation and (ii) the use of anti-inflammatory drugs to reduce ocular surface inflammation.
  • current dry eye treatment involves topical application of artificial tear products/lubricants, tear retention management, stimulation of tear secretion, topical application of antibiotics (e.g., erythromycin or bacitracin ointments), oral administration of tetracyclines (e.g., tetracycline, doxycycline, or minocycline), application of a calcineurin inhibitor immunosuppressant, such as cyclosporine, and corticosteroids.
  • antibiotics e.g., erythromycin or bacitracin ointments
  • tetracyclines e.g., tetracycline, doxycycline, or minocycline
  • a calcineurin inhibitor immunosuppressant such as cyclosporine, and corticosteroids.
  • Lifitegrast (chemical name: N- ⁇ [2-(l-Benzofuran-6-ylcarbonyl)-5,7- dichloro-l,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl ⁇ -3-(methylsulfonyl)-L-phenylalanine) ophthalmic solution 5.0% has been reported to improve symptoms of ocular discomfort and eye dryness compared with placebo when administered twice daily (Sheppard et al., Ophthalmology , 2014, 121(2), pp. 475-483).
  • DED Dry eye disease
  • aqueous tear deficient DED aqueous tear deficient DED
  • evaporative DED aqueous tear deficient DED
  • DED is often a result of changes to the lacrimal functional unit, or LFU.
  • the LFU is composed of the lacrimal glands, cornea, eyelids, meibomian glands, conjunctiva, goblet cells and ocular nerves. The LFU is responsible for the sustained production of adequate tear film to consistently lubricate the ocular surface.
  • Structural changes to the LFU can induce tear film instability and insufficiency, which in turn can lead to tear hyperosmolarity.
  • Various stresses to the ocular surface such as environmental factors, infection, endogenous stress, antigens, genetic factors are identified as primary pathogenic triggering cause.
  • Chronic osmotic stress from tear film can activate stress-associated pathways in ocular surface epithelial cells, thereby triggering a pro- inflammatory response that involves a mix of chemokines, cytokines, and matrix
  • the subsequent maturation of antigen-presenting cells on the ocular surface leads to the migration, activation and expansion of autoreactive T cell lymphocytes as well as other leukocytic classes in the LFU.
  • the constant recruitment of pro-inflammatory leukocytes onto the ocular surface may inflict epithelium damage in the form of small abrasions and epithelium barrier defects. These abrasions can eventually progress to superficial punctuate keratitis, squamous metaplasia, extracellular matrix (“ECM”) deposits, decreased goblet cell differentiation, increased epithelial cell turnover (epitheliopathy) and significant ocular surface nerve damage and neuropathy.
  • ECM extracellular matrix
  • the current invention in directed to a combination formulation consisting two or more APIs with different molecular targets for the pathogenesis of DED.
  • Combination of two or more APIs with different mechanism of action in single formulation provides regulations of more than one molecular pathway and provides a significant benefit to DED patients.
  • some embodiments of the present invention is directed to a selection of APIs in combination formulations targeting multiple molecular pathways involved in pathophysiology ocular surface diseases, anterior segment of eye diseases as well as pain and inflammation associated with ocular surgery.
  • One particular aspect of the present invention provides an ophthalmic
  • composition comprising at least two active pharmaceutical ingredients.
  • the at least two active pharmaceutical ingredients are selected from a different classification.
  • the active pharmaceutical ingredients are selected from the following classification of active pharmaceutical ingredients: an alpha 2 adrenergic receptor agonist; a beta-adrenergic receptor agonist; an immunosuppressant; a lymphocyte associated antigen antagonist; an anti-inflammatory; a beta-blocker; a prostaglandin analog; a histamine receptor antagonist; a carbonic anhydrase inhibitor; and an antibiotic.
  • the composition of the invention is a nanoemulsion formulation.
  • a nanoemulsion formulation of the invention provides a wide variety of surprising an unexpected benefits including, but not limited to, extended release of active pharmaceutical ingredients, better penetration profile of the active pharmaceutical ingredient(s) to the desired cells, increased resident time in the cornea, etc.
  • the composition of the invention is an ophthalmic nanoemulsion formulation.
  • a first active pharmaceutical ingredient is said alpha 2 adrenergic agonist
  • a second active pharmaceutical ingredient is selected from the group consisting of: said immunosuppressant, said lymphocyte associated antigen agonist, said corticosteroid, said beta-blocker, said prostaglandins analog, said carbonic anhydrase inhibitor, and a combination thereof.
  • the alpha 2 adrenergic agonist comprises brimonidine, a pharmaceutical salt thereof, or a combination thereof.
  • the immunosuppressant is selected from the group consisting of cyclosporine, tacrolimus, and a combination thereof.
  • the lymphocyte associated antigen agonist comprises Lifitegrast.
  • the corticosteroid is selected from the group consisting of prednisolone, methylprednisolone, difluprednate, prednisone acetate, prednisolone sodium phosphate, triamcinolone, fluocinolone; fluorometholone, betamethasone, medrysone, and a combination thereof.
  • the anti-inflammatory is selected from a group consisting of a corticosteroid, a non-steroidal anti inflammatory drug (“NS AID”), thymosin beta 4, and a combination thereof.
  • the NSAID is selected from the group consisting of diclofenac, flubiprofen, ketorolac, ketorolac thromethamine, bromfenac, nepafenac, flurbiprofen, and a combination thereof.
  • the beta-adrenergic receptor agonist is selected from the group consisting of Dopexamine, Epinephrine, Isoprenaline, isoproterenol, levalbuterol, Salbutamol, albuterol, and a combination thereof.
  • the beta-blocker is selected from the group consisting of Timolol, Propranolo, Sotalol, nadolol, and a combination thereof.
  • the prostaglandins analog is selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, and a combination therof.
  • the carbonic anhydrase inhibitor is selected from the group consisting of dorzolamide, methazolamide, brinzolamide, dichlorphenamide, and a combination thereof.
  • the active pharmaceutical ingredients consist of (i) brimonidine, a pharmaceutically acceptable salt thereof, or a combination thereof; (ii) cyclosporine; and (iii) Lifitegrast or Loteprednol.
  • One particular aspect of the invention provides an aqueous ophthalmic solution comprising (i) brimonidine, a pharmaceutically acceptable salt thereof, or a combination thereof and (ii) cyclosporine.
  • the aqueous ophthalmic solution is a nanoemulsion solution.
  • compositions of the invention can also include a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient comprises: an emulsion stabilizing polymer, a water-soluble polymer, a surfactant, a tonicity modifier or a stabilizer, a viscosity modifier, or a combination thereof.
  • the pharmaceutically acceptable excipient comprises (i) an emulsion stabilizing polymer; (ii) a surfactant; (iii) a tonicity modifier or a stabilizer selected from the group consisting of a polyol, a non-reducing disaccharide and a combination thereof; or (iv) a combination thereof.
  • the pharmaceutically acceptable excipient comprises polysorbate 80, Pemulen®, carbomer copolymer type A, a polyol or a combination thereof. Yet in other embodiments, the pharmaceutically acceptable excipient comprises polysorbate 80, Pemulen®, carbomer copolymer type B, a polyol or a combination thereof. Still in other embodiments, the tonicity modifier or a stabilizer is selected from the group consisting of a polyol, a non-reducing disaccharide, and a combination thereof. Yet still in other embodiments, the viscosity modifier is selected from the group consisting of carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, and a combination thereof. Still yet in other
  • the surfactant is selected from the group consisting of: (i) a nonionic surfactant, such as glyceryl laurate, polysorbate, spans, poloxamers, Nonoxynol-9; (ii) a cationic surfactant such as benzalkonium chloride, benzethonium chloride, benzododecinium bromide, cetrimonium bromide, cetrimonium chloride, tetramethylammonium hydroxide, lauralkonium chloride; (iii) a zwitterionic surfactant such as lecithin; and (iv) a combination thereof. Still in other suitable surfactant such as lecithin;
  • the pharmaceutically acceptable excipient comprises (i) an emulsion stabilizing polymer, (ii) a surfactant, (iii) a tonicity modifier or a stabilizer selected from the group consisting of a polyol, a non-reducing disaccharide, and a combination thereof, or (iv) a combination thereof.
  • Still another aspect of the invention provides a method for treating a clinical condition associated with eye, such as an eye disorder or an eye disease.
  • the method includes administering to a subject in need of such a treatment a therapeutically effective amount of a composition of the invention.
  • the clinical condition associated with eye is selected from the group consisting of dry eye syndrome (e.g., keratoconjunctivitis sicca), sjogren’s syndrome, congenital alacrima, xerophthalmia (dry eye from vitamin A deficiency), keratomalacia, thyroid eye disease, ocular rosacea, eyelid disorders, meibomian gland disease, meibomian gland dysfunction, ectropion, blepharitis, blepharochalasis, sarcoidosis, stye, hordeolum, chalazion, ptosis, pterygium, eyelid edema, eyelid dermatitis, trichiasis, madarosis, dacryoadenitis, stevens-johnson syndrome, ocular graft versus host disease, dacryocystitis, conjunctivitis, keratoconjunctivis, ker
  • ocular surface conditions caused by chemical bums, thermal burns or physical trauma ocular conditions caused by the following autoimmune or vascular disorders: rheumatoid arthritis, juvenile rheumatoid arthritis, ankulosing spondylitis, reiter’s syndrome, enteropathic arthritis, psoriatic arthritis, discoid and systemic lupus erythematosus, multiple sclerosis, graves’ disease, antiphospholipid syndrome, sarcoidosis, wegner’s granulomatosis, behcet’s syndrome, polyarteritis nodosa, takayasu’s arteritis, dermatomyositis, psoriasis, relapsing polychondritis, vasculitis, sickle cell-
  • the dry eye syndrome is selected from the group consisting of sjogren’s syndrome, meibomian gland dysfunction and keratoconjunctivitis. Still in other embodiments, the eyelid disorder comprises eyelid inflammation, pain and/or edema.
  • the composition is administered topically to an eye of said subject.
  • the composition is formulated as a homogeneous ophthalmic aqueous formulation.
  • the composition is formulated as a heterogeneous ophthalmic aqueous solution.
  • the heterogeneous ophthalmic aqueous solution comprises emulsion, suspension or a combination thereof.
  • Figure 1 is a table showing measured median diameter of particle size distribution
  • Figure 2 is a table showing median diameter of particle size distribution [Dx(50)] of an ophthalmic nanoemulsion formulation of brimonidine tartrate and loteprednol etabonate at different temperatures (RT is room temperature) at days 0, 36 and 66.
  • Figure 3 is a table shows measured median diameter of particle size distribution
  • Figure 4 is a table showing partitioning of brimonidine tartrate and cyclosporine in various phases, oil and aqueous, of (i) combination of brimonidine tartrate (0.2 % w/w) and 0.05% w/w cyclosporine ophthalmic nanoemulsion formulation and (ii) combination of brimonidine tartrate (0.2% w/w) and 0.1% w/w cyclosporine ophthalmic nanoemulsion formulation.
  • Figure 5 shows stability data at different temperatures of an ophthalmic nanoemulsion formulation of the present invention consisting of active pharmaceutical ingredients brimonidine tartrate and cyclosporine.
  • Figure 6A is a graph showing particle size distribution [Dx(50)] of an ophthalmic nanoemulsion formulation of the present invention having active pharmaceutical ingredients brimonidine tartrate and loteprednol etabonate.
  • Figure 6B is a graph showing particle size distribution [Dx(50)] of an ophthalmic nanoemulsion formulation of the present invention having active pharmaceutical ingredients brimonidine tartrate (0.2 % w/w) and 0.05% w/w cyclosporine.
  • Figure 6C is a graph showing particle size distribution [Dx(50)] of an ophthalmic nanoemulsion formulation of the present invention having active pharmaceutical ingredients (B) brimonidine tartrate (0.2% w/w) and 0.1% w/w cyclosporine.
  • One aspect of the invention provides a nanoemulsion ophthalmic composition comprising at least two active pharmaceutical ingredients.
  • nanoemulsion refers to emulsion having a median emulsion droplet particle size (i.e., Dx(50)) of about 250 nm or less, typically about 220 nm or less, often about 200 nm or less, and most often about 100 nm or less.
  • Dx(50) median emulsion droplet particle size
  • the active pharmaceutical ingredients are selected from the following classification of active pharmaceutical ingredients: an alpha 2 adrenergic receptor agonist; a beta-adrenergic receptor agonist; an immunosuppressant; a lymphocyte associated antigen antagonist; an anti-inflammatory; a beta-blocker; a prostaglandin analog; a histamine receptor antagonist; a carbonic anhydrase inhibitor; and an antibiotic.
  • the composition of the invention comprises an alpha 2 adrenergic receptor agonist in combination with one or more of a calcineurin inhibitor (e.g., cyclosporine) and a lymphocyte function-associated antigen antagonist (e.g., lifitegrast).
  • the composition of the invention comprises an alpha 2 adrenergic receptor agonist in combination with a corticosteroid.
  • Still another aspect of the invention provides a composition comprising an alpha 2 adrenergic receptor agonist in combination with one or more of the following components: (i) a calcineurin inhibitor; (ii) a lymphocyte function-associated antigen antagonist; (iii) an anti inflammatory (e.g., corticosteroid comprising loteprednol, thymosin beta 4, etc.); (iv) a sodium channel blocker; (v) a non-steroidal anti-inflammatory drug (i.e., NSAID); and (vi) an antihistamine.
  • a calcineurin inhibitor e.g., a lymphocyte function-associated antigen antagonist
  • an anti inflammatory e.g., corticosteroid comprising loteprednol, thymosin beta 4, etc.
  • a sodium channel blocker e.g.
  • the anti-inflammatory is a corticosteroid. Still in other embodiments, the anti-inflammatory is an NSAID. Yet in other embodiments, the anti inflammatory is thymosin beta 4.
  • compositions of the invention are heterogeneous solution formulations, containing a combination of therapeutically effective amount of active pharmaceutical components in the formulation.
  • compositions of the invention are homogeneous aqueous formulations, containing a combination of therapeutically effective amount of active pharmaceutical components in the formulation.
  • compositions or formulations of the invention can contain just two active ingredients or more than two active ingredients.
  • at least one of the active ingredient is an alpha 2 adrenergic receptor agonist such as brimonidine, or a pharmaceutically acceptable salt there of or a combination thereof.
  • compositions of the invention are useful for treatment of various eye disorders or eye diseases including, but not limited to, dry eye syndrome (keratoconjunctivitis sicca), sjogren’s syndrome, congenital alacrima, xerophthalmia (dry eye from vitamin A deficiency), keratomalacia, thyroid eye disease, ocular rosacea, eyelid disorders, meibomian gland disease, meibomian gland dysfunction, ectropion, blepharitis, blepharochalasis, sarcoidosis, stye, hordeolum, chalazion, ptosis, pterygium, eyelid edema, eyelid dermatitis, trichiasis, madarosis, dacryoadenitis, stevens-johnson syndrome, ocular graft versus host disease, dacryocystitis, conjunctivitis, keratocon
  • ocular surface conditions caused by chemical bums, thermal burns or physical trauma ocular conditions caused by the following autoimmune or vascular disorders: rheumatoid arthritis, juvenile rheumatoid arthritis, ankulosing spondylitis, reiter’s syndrome, enteropathic arthritis, psoriatic arthritis, discoid and systemic lupus erythematosus, multiple sclerosis, graves’ disease, antiphospholipid syndrome, sarcoidosis, wegner’s granulomatosis, behcet’s syndrome, polyarteritis nodosa, takayasu’s arteritis, dermatomyositis, psoriasis, relapsing polychondritis, vasculitis, sickle cell-
  • Some aspects of the invention provide a method for treating dry eye syndrome using the compositions disclosed herein.
  • dry eye syndrome There are two major classes of dry eye syndrome: (i) aqueous tear-deficient dry eye (ADDE) and (ii) evaporative dry eye (EDE).
  • ADDE aqueous tear-deficient dry eye
  • EDE evaporative dry eye
  • ADDE mixed mechanism dry eye
  • ADDE is primarily due to failure of lacrimal tear secretion.
  • ADDE can be further subdivided into Sjogren syndrome dry eye (where the lacrimal and salivary glands are targeted by an autoimmune process, e.g., rheumatoid arthritis) and non-Sjogren's syndrome dry eye (lacrimal dysfunction, but the systemic autoimmune features of Sjogren's syndrome are excluded, e.g., age-related dry eye).
  • EDE is primarily due to excessive water loss from the exposed ocular surface in the presence of normal lacrimal secretory function. Its causes can be extrinsic (e.g., ocular surface disorder due to some extrinsic exposure, contact lens wear or vitamin A deficiency) or intrinsic (e.g.,
  • Meibomian gland dysfunction and disorders of eyelid aperture Meibomian glands secrete a mixture of lipids and other components that form the outer layer of the preocular tear film. This lipid layer functions to decrease tear film evaporation.
  • Meibomian gland dysfunction (MGD) leads to evaporative dry eye disease.
  • MGD meibomian gland dysfunction
  • MGD ocular graft-versus-host-disease
  • compositions of the invention include keratoconjunctivitis, dry eye caused by conjunctivitis, dry eye caused by allergic conjunctivitis, dry eye caused by blepharitis, dry eye caused by keratitis, dry eye caused by dacryoadenitis, dry eye caused by ocular rosacea, dry eye caused by boehm syndrome, dry eye caused by conjunctivochalasis, dry eye caused by blepharoconjunctivitis, dry eye caused by blepharokeratoconjunctivitis, dry eye caused by superficial punctuate keratitis, dry eye caused by thygeson’s superficial punctuate keratopathy, dry eye caused by oGVHD, Sjogren’s dry eye syndrome, dry eye caused by Stevens- Johnson syndrome, MGD, dry eye caused by meibomian gland disease, vitamin A deficiency induced dry eye, pharmacological induced dry eye (i.e.
  • hormone replacement therapy blood pressure medication, antihistamine, antidepressants, anticholinergic medications, glaucoma medication, antihypertensives, diuretics, sedatives, isotretinoin, nasal decongestants, oral contraceptives, beta-blockers, phenothiazines, atropine, pain relieving opiates), pregnancy induced dry eye, LASIK surgery or refractive surgery induced dry eye, dry eye induced by collagen vascular diseases (i.e.
  • methods for treating dry eye syndrome comprise treating a patient in need of a treatment for Meibomian gland dysfunction (MGD).
  • methods for treating dry eye syndrome comprise treating a patient in need of a treatment for aqueous tear-deficient dry eye (ADDE).
  • methods for treating ADDE comprise treating a patient in need of a treatment for Sjogren dry eye syndrome, ocular Graft- Versus-Host-Disease (oGVHD) or non-Sjogren dry eye syndrome.
  • methods for treating dry eye syndrome comprise treating a patient in need of a treatment of evaporative dry eye (EDE).
  • methods of the invention include treating a patient in need of a treatment for mixed mechanism dry eye consisting of ADDE and EDE. Yet still in other embodiments, methods of the invention include treating a patient suffering from dry eye syndrome due to a complication of refractive eye surgery, or is attributable to one or more of the following causes: vitamin A deficiency, ocular surface disorders, allergy, aging, contact lens usage, medication usage or eyelid disorders.
  • compositions of the invention include an alpha 2 (a2) adrenergic receptor agonists.
  • alpha 2 adrenergic receptor agonists include, but are not limited to, brimonidine, 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol, rilmenidine, romifidine, talipexole, tizanidine, tolonidine, xylazine, xylometazoline, and the like including pharmaceutically acceptable salts thereof.
  • the alpha 2 adrenergic receptor agonist is brimonidine (5-Bromo-/V-(4, 5-dihydro- l//-imidazol-2-yl) quinoxalin-6-amine), a
  • “Pharmaceutically acceptable salt” of a compound means a salt that is
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyljbenzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
  • ethanesulfonic acid l,2-ethane-disulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
  • Particular examples of pharmaceutically acceptable salts of brimonidine include, but not limited to, tartrate salt, trifluoroacetate salt, hydrochloric salt, acetate salt, oxalic acid salt, as well as others disclosed herein and/or known to one skilled in the art.
  • Alpha-2 adrenergic receptor agonists are those compounds that activate alpha-2 adrenergic receptors. There are three subtypes of this receptor, designated A, B, and C. An alpha-2 adrenergic receptor agonist that can activate any or all of these receptor subtypes can be used in the present invention. However, in some embodiments of the invention, an alpha 2 adrenergic receptor agonist has a higher activity or efficacy at the alpha-2A adrenergic receptor subtype compared to its activity at the alpha-2B receptor subtype (e.g., brimonidine and its salts).
  • alpha-2A adrenergic receptor subtype e.g., brimonidine and its salts.
  • the alpha 2 adrenergic agonist in compositions of the invention has a higher alpha 2 A agonist activity compared to alpha 2B agonist activity.
  • the alpha 2A agonist activity of the alpha 2 adrenergic agonist is at least about 10% greater, typically at least about 20% greater and often at least about 30% greater than its alpha 2B agonist activity.
  • the term“about” when referring to a numeric value means ⁇ 20%, typically ⁇ 10%, often ⁇ 5% and most often ⁇ 2% of the numeric value.
  • the second pharmaceutically active compound comprises a calcineurin inhibitor, a lymphocyte function-associated antigen antagonist, or a combination thereof.
  • Calcineurin is a calmodulin and calcium dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase). It activates the T cells of the immune system and can be blocked by a class of drugs called calcineurin inhibitors, which includes cyclosporine, tacrolimus, pimecrolimus, voclosporin, as well as others known to one skilled in the art.
  • calcineurin inhibitors e.g., cyclosporine
  • LFA Lymphocyte function-associated antigen
  • IAM intercellular adhesion molecule
  • lymphocyte function-associated antigen antagonists include, but are not limited to, lifitegrast (i.e., (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid), which is a water-soluble drug that blocks LFA-l from binding to ICAM-l, and other lymphocyte function-associated antigen antagonists that are known to one skilled in the art. Any lymphocyte function-associated antigen can be used in compositions of the invention.
  • composition of the invention is formulated as an aqueous solution, which can be a homogeneous or heterogeneous solution.
  • aqueous solution which can be a homogeneous or heterogeneous solution.
  • compositions of the invention include at least two active ingredients.
  • the formulation contains one active ingredient that is water soluble and the another active ingredient that is a lipophilic.
  • the formulation contains two or more active ingredients that are water soluble.
  • the formulation contains two or more active ingredients that are lipophilic.
  • compositions of the invention are formulated as an aqueous ophthalmic solution. As stated above, the aqueous ophthalmic solution can be homogenous or
  • heterogeneous can include aqueous suspension or dispersion, where at least some of the active ingredients are present as suspension or dispersion in aqueous solution.
  • the aqueous ophthalmic solution can be a substantially homogeneous aqueous solution, where substantially all (i.e., 385%, typically 3 90%, often > 95%, and most often > 97%) of the active ingredients are dissolved in the aqueous solution.
  • one of the active ingredients is brimonidine, its pharmaceutically acceptable salt thereof or a combination thereof.
  • the composition includes a second active ingredient that can be cyclosporine, lifitegrast or a combination thereof.
  • the terms“active ingredient” and“active pharmaceutical ingredient” are used interchangeably herein and refer to a compound that is used or known to one skilled in the art in treating an eye disorder, such as dry eye syndrome.
  • an eye disorder such as dry eye syndrome.
  • water and oil can be present in some formulations, they are not used primarily for the purpose of treating eye disorder but are used as a vehicle to carry active ingredients.
  • an active ingredient works on a particular receptor or cells or has been approved for treating an eye disorder by the U.S. Food and Drug Administration (“FDA”).
  • FDA U.S. Food and Drug Administration
  • the term“active ingredient” refers to an alpha 2 adrenergic receptor agonist; a beta-adrenergic receptor agonist; an immunosuppressant; a lymphocyte associated antigen antagonist; an anti-inflammatory (e.g., corticosteroid, NSAID, thymosin beta 4, etc.); a beta-blocker; a prostaglandin analog; a histamine receptor antagonist; a carbonic anhydrase inhibitor; and an antibiotic.
  • the term“active ingredient” refers to: an alpha 2 adrenergic agonist; a calcineurin inhibitor; a lymphocyte function-associated antigen antagonist; a corticosteroid; CRGP receptor antagonists; anti-CGRP receptor monoclonal antibodies; an inhibitor of adrenomedullin, serotonin, cathelicidin or neuropeptides; a sodium channel blocker; an antihistamine; and/or a non-steroidal anti inflammatory drug.
  • ingredients that may be present in formulations/compositions of the invention are used primarily as pharmaceutically acceptable excipients or vehicles, such as a pH adjusting agent, a tonicity modifier or a stabilizer, a surfactant, an emulsion stabilizer, etc.
  • composition of the invention is formulated as a heterogeneous aqueous solution.
  • the composition of the invention include from about 0.01 to about 5 mg/mL (about 0.001% to about 0.5% w/v) typically about 0.2% w/v or less (e.g., 0.05-0.2% often 0.07-0.15%) of brimonidine or a salt thereof (e.g., brimonidine tartrate and hydroxy brimonidine trifluoroacetate).
  • brimonidine or a salt thereof e.g., brimonidine tartrate and hydroxy brimonidine trifluoroacetate.
  • the ingredient amounts are presented in units of either % weight/volume (% w/v) or weight/weight (% w/w).
  • brimonidine tartrate is used as an alpha 2 adrenergic agonist.
  • the amount of brimonidine tartrate present in the composition is from about 0.01% w/w to about 1% w/w, typically from 0.01% w/w to about 0.7% w/w, and often from about 0.02% to about 0.5% w/w.
  • the second therapeutically active compound comprises cyclosporine.
  • the second therapeutically active compound comprises cyclosporine A.
  • a typical amount of cyclosporine A present in the composition of the invention is from about 0.005% w/w to about 0.5% w/w, often from about 0.01% w/w to about 0.3% w/w.
  • the second therapeutically active compound comprises lifitegrast®.
  • the amount of lifitegrast present in compositions of the invention is from about 0.1% w/w to about 20% w/w, typically from about 0.2% w/w to about 15% w/w, and often from about 0.3% w/w to about 10% w/w.
  • the second therapeutically active compound comprises a corticosteroid.
  • corticosteroids include, but are not limited to, methylprednisolone, hydrocortisone, betamethasone, dexamethasone and loteprednol etabonate.
  • the corticosteroid used in the composition of the invention is loteprednol etabonate.
  • the amount of loteprednol etabonate present in the compositions of the invention is from about 0.01% w/w to 2% w/w; typically from about 0.05% w/w to 1%, and often from about 0.1% to about 0.3%.
  • the second therapeutically active compound comprises a sodium channel blocker and/or mucolytic agents.
  • Suitable sodium channel blockers and/or mucolytic agents for treatment of eye disorder are known to one skilled in the art and include those disclosed, for example, in U.S. Patent Nos. 9,586,911, 9,346,753, 8,980,898,
  • Suitable sodium channel blockers for the present invention include, but are not limited to amiloride, benzamil, phenamil, amiloride analogues, as well as those disclosed in US Patent Nos.
  • the second therapeutically active compound comprises a non-steroidal anti-inflammatory drug (i.e., NSAID).
  • NSAIDs that are useful in treating eye disorder include ketorolac (0.05 to 0.3%), diclofenac (0.01 to 1%), flurbiprofen (0.01 to 1%), bromfenac (0.01 to 0.5%), nepafenac (0.05 to 0.5%), etc.
  • Acular, Acular PF, and Acular LS ketonesolac tromethamine, Allergan
  • Ocufen flurbiprofen sodium, Allergan
  • Voltaren diclofenac sodium, Novartis
  • Xibrom bromfenac ophthalmic solution, Ista Pharmaceuticals
  • Prolensa bromfenac ophthalmic solution, Bausch & Lomb
  • Nevanac Nevanac
  • the second therapeutically active compound comprises an antihistamine.
  • Suitable antihistamines that are useful in treating eye disorder include alcaftadine (0.01 to 0.5%), azelastine (0.001% to 0.2%), bepotastine (0.1% to 3%), emedastine (0.001% to 0.2%), epinastine (0.001% to 0.2%), ketotifen (0.001% to 0.2%), and olopatadine (0.01% to 1.5%).
  • Lastacaft alcaftadine, Allergan
  • Optivar zelastine hydrochloride, Meda Pharmaceuticals
  • Bepreve bepotastine besilate, Bausch & Lomb
  • Emadine emedastine difumarate, Alcon
  • Elestat epinastine hydrochloride, Allergan
  • Alaway ketotifen fumarate, Baush & Lomb
  • Zaditor ketotifen fumarate, Alcon
  • Pazeo olopatadine hydrochloride, Alcon
  • Pataday olopatadine hydrochloride, Alcon
  • Patanol olopatadine hydrochloride, Alcon
  • the second therapeutically active compound comprises thymosin beta 4.
  • the amount of thymosin beta 4 present in the first therapeutically active compound comprises thymosin beta 4.
  • compositions of the invention is from about 0.01% w/w to 2% w/w; typically from about 0.05% w/w to 1%, and often from about 0.0.05% to about 0.3%.
  • the second therapeutically active compound comprises a prostaglandin analog.
  • prostaglandin analogs that are useful in compositions of the invention include, but are not limited to, latanoprost, bimatoprost, travoprost, and tafluprost.
  • the amount of prostaglandin analog in the compositions of the invention is from about 0.001% w/w to 1% w/w; typically from about 0.005% w/w to 0.5%, and often from about 0.005% to about 0.1%.
  • compositions of the invention are used as an ophthalmic formulation.
  • Such ophthalmic formulations can be homogeneous or heterogeneous formulations.
  • the formulated composition contains an oil or a fatty acid ester.
  • a fatty acid ester has the meaning commonly understood in the art, being an ester formed between an alcohol and a fatty acid.
  • Exemplary fatty acid esters that are useful in formulations of the invention include, but are not limited to, triglyceride esters commonly known as vegetable oils, mono and diglyceride esters of fatty acids, fatty acid methyl esters, as well as other fatty acid esters that are known to one skilled in the art.
  • the fatty acid ester can be a mixture of several chemical compounds or an essentially pure compound.
  • the fatty acid ester is a vegetable oil.
  • vegetable oils that can be used include, but are not limited to, castor oil, sesame oil, soybean oil, cottonseed oil, olive oil, peanut oil, safflower oil, sunflower oil, palm oil, palm kernel oil, canola oil, and Miglyol oil ® .
  • the fatty acid ester is castor oil.
  • Various vehicles can be used in the ophthalmic formulations of the present invention. These vehicles include, but are not limited to, purified water (water), polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, cyclodextrin and a mixture of two or more thereof.
  • the vehicle is used in the formulation in amounts as needed to provide the concentration of the active compound(s) disclosed herein.
  • the vehicle comprises water.
  • an emulsion stabilizing polymer is used.
  • emulsion stabilizing polymers generally contain hydrophilic groups such as cellulose, sugars, ethylene oxide, hydroxide, carboxylic acids or other polyelectrolytes. Without being bound by any theory, it is believed that these polymers help to stabilize emulsions by increasing the viscosity of the formulation as well as by reducing the interfacial tension.
  • Some examples of emulsion stabilizing polymers useful in this invention include, but are not limited to, carbomers, Pemulen ® , sodium carboxymethylcellulose, hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, polyethylene glycol and a mixture of two or more thereof.
  • Pemulen ® (B.F. Goodrich, Cleveland, OH) is used as the polymeric based stabilizer.
  • Pemulen ® are Acrylates/Cio-30 Alkyl Acrylate Cross-Polymers.
  • the formulation comprises a surfactant.
  • a surfactant is used to help facilitate the formation of the emulsion and improve its stability.
  • Any type of surfactant can be used including, anionic, cationic, amphoteric, zwitterionic, nonionic, as well as a mixture of two or more thereof.
  • the formulation of the invention comprises a nonionic surfactant.
  • nonionic surfactants include, but are not limited to, polysorbates, poloxamers, alcohol ethoxylates, ethylene glycol-propylene glycol block copolymers, fatty acid amides, alkylphenol ethoxylates, phospholipids, and two or mixture thereof.
  • the surfactant is Polysorbate 80 (ICI Americas, Inc., Wilmington, DE).
  • useful buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers.
  • a buffering agent is used to maintain the pH in the therapeutically useful range of pH 4-10, typically about pH 5-8, often a pH range of 6.5 -8.0, more often a pH range of 7.0-8.0, and most often a pH range of 7.2 -7.6. It should be appreciated, however, that the scope of the invention is not limited to these particular pH ranges. In general, any pH range that provides suitable penetration of the active ingredient(s) through the eye can be used.
  • a buffering agent known to those skilled in the art is used including, but not limited to, acetate, borate, tris, carbonate, citrate, histidine, succinate, and phosphate.
  • the buffering agent comprises boric acid.
  • the buffering agent comprises sodium citrate.
  • the pH of the ophthalmic formulation can be adjusted by addition of an acid or a base in quantity sufficient to achieve the desired pH.
  • the pH adjustment can be achieved through use of various chemicals such as hydrochloric acid, sodium hydroxide, citric acid, sodium citrate, acetic acid, sodium acetate, ammonium acetate, succinic acid, lactic acid, calcium lactate, sodium lactate, sodium fumarate, sodium propionate, boric acid, tris base, ammonium borate, maleic acid, phosphoric acid, sulfuric acid and aluminum potassium sulfate and the like.
  • a specific example of an acid that can be used to adjust the pH of the aqueous buffered ophthalmic formulation is 1 N hydrochloric acid.
  • a specific example of a base that can be used to adjust the pH of the aqueous buffered ophthalmic formulation is 1 N sodium hydroxide.
  • any pharmaceutically acceptable acids and bases can be used to adjust the pH.
  • the ophthalmic formulations of the present invention contain a combination of dibasic and monobasic phosphate or boric acid and sodium borate - as buffering agents.
  • the formulations contain an amount of boric acid and sodium borate sufficient to buffer the formulation in a pH range of 6.5-8.0 or 7.5-8.0 or dibasic and monobasic phosphate sufficient to buffer the formulation in a pH range of 6.5-8.0 or 7.0-8.0 or 7.5-8.0.
  • a tonicity agent (tonicity-adjusting agent) is used to adjust the composition of the formulation to the desired isotonic range.
  • the tonicity-adjusting agent can be a polyol or a disaccharide including non-reducing disaccharides.
  • Such tonicity agents are known to one skilled in the art, and include, but are not limited to, glycerin, mannitol, sorbitol, trehalose, xylitol, sodium chloride, and other electrolytes.
  • the tonicity agent is glycerin.
  • gum and/or resin can be included in the formulations of the invention, including for example, sodium polyacrylate, cellulose ether, calcium alginate, carboxyvinyl polymer, ethylene-acrylic acid copolymer, vinyl pyrrolidone polymer, vinyl alcohol-vinyl pyrrolidone copolymer, nitrogen-substituted acrylamide polymer, polyacrylamide, cationic polymer such as cationic guar gum, dimethylacrylic ammonium polymer, acrylic acid- methacrylic acid copolymer, polyoxyethylene-polypropylene copolymer, polyvinyl alcohol, pullulan, agar, gelatine, chitosan, polysaccharide from tamarindo seed, xanthan gum, carageenan, high-methoxyl pectin, low-methoxyl pectin, guar gum, acacia gum, microcrystalline cellulose, arabinogalactan, karaya gum,
  • the formulations are preservative-free.
  • a preservative is used.
  • Preservatives are used, for example, to prevent bacterial contamination in multiple-use ophthalmic preparations.
  • Exemplary preservatives include, but are not limited to, benzalkonium chloride, stabilized oxychloro complexes (otherwise known as Purite ® ), phenylmercuric acetate, chlorobutanol, benzyl alcohol, parabens, and thimerosal.
  • the preservative is Purite ® .
  • chelating agents include, but are not limited to, edetate salts like edetate disodium, edetate calcium disodium, edetate sodium, edetate trisodium, and edetate dipotassium.
  • the chelating agent is edentate disodium. It should be appreciated that other chelating agents may also be used in place of or in conjunction with edentate disodium.
  • antibiotics that can be included in formulations of the invention include, but are not limited to, trimethoprim sulfate/polymyxin B sulfate, gatifloxacin, moxifloxacin hydrochloride, tobramycin, teicoplanin, vancomycin, azithromycin, clarithromycin, amoxicillin, penicillin, ampicillin, carbenicillin, ciprofloxacin, levofloxacin, amikacin, gentamicin, kanamycin, neomycin and streptomycin.
  • the formulations of the present invention can be packaged in various package forms known in the field of topical ophthalmics.
  • the formulation is packaged in sterile, preservative-free single-use packs or vials or containers (i.e., the unit dose vials).
  • Each vial for example as small as a 0.9 mL, may be made of low density polyethylene so as to contain a small quantity of the formulation, e.g., 0.4 mL for a single use.
  • BFS blow-fill-seal
  • the formulation is packaged in multi-dose vials such that the materials can be dispensed as sterile at each time using specialized container/ closure maintaining the sterility integrity.
  • the formulation is packed in conventional vials / containers as sterile product.
  • the dosage form of the invention is eye drops of heterogeneous aqueous solution, eye drop formulations containing two or more active ingredients in which the first active ingredient is an alpha 2 adrenergic receptor agonist and a second active ingredient is selected from the group consisting of a calcineurin inhibitor, a lymphocyte function-associated antigen antagonist, a corticosteroid, NSAID, a sodium channel blocker, an anti-histamine, and a combination of two or more thereof.
  • an eye drop formulations can contain bromonidine or brimonidine tartrate and cyclosporine, or bromonidine or brimonidine tartrate and lifitegrast or cyclosporine and lifitegrast combination or brimonidine or brimonidine tartrate, cyclosporine and lifitegrast.
  • Eye drops typically contain, according to the invention, aqueous / oily suspensions of the active ingredients in pharmaceutically acceptable carriers and/or excipients.
  • the particle size of the active ingredient employed is about 10 pm or less, typically 5 pm or less, often 1 pm or less, more often 0.5 pm or less, still more often 0.2 pm or less and most often 0.15 pm or less
  • the invention relates to methods of treating a subject or human patient suffering from an eye disorder (e.g., dry eye syndrome) by administering to the eye of the patient an ophthalmic formulation disclosed herein.
  • formulations used in treating an eye disorder comprise (i) brimonidine or a pharmaceutically acceptable salt thereof (e.g., brimonidine tartrate) and cyclosporine, (ii) brimonidine or a pharmaceutically acceptable salt thereof and lifitegrast, (iii) cyclosporine and lifitegrast combination or (iv) all three actives, i.e., brimonidine or a pharmaceutically acceptable salt thereof, cyclosporine and lifitegrast.
  • compositions of the invention include brimonidine or a pharmaceutically acceptable salt thereof and loteprednol; a combination of brimonidine a pharmaceutically acceptable salt thereof and an NS AID; and a combination of brimonidine a pharmaceutically acceptable salt thereof and a sodium channel blocker and brimonidine or a pharmaceutically acceptable salt there of and an antihistamine.
  • the active ingredients are present in an amount effective to provide a desired therapeutic benefit to a patient suffering from an eye disorder to whom the composition is administered.
  • the therapeutically effective amount should be sufficient to realize relief from the eye disorder after the treatment.
  • the eye of a subject or human patient can be the entire eye structure or a tissue or gland in or around the eye such as the ocular tissue, eyelids, margin of the eyelid of the subject, ocular surface.
  • the ophthalmological pharmaceutical formulation is topically administrable and/or is administered in, on or around the eye.
  • the dry eye syndrome can be aqueous tear-deficient dry eye (ADDE) or evaporative dry eye (EDE) or consists of both ADDE and EDE (mixed mechanism dry eye).
  • ADDE may be Sjogren syndrome dry eye (where the lacrimal and salivary glands are targeted by an autoimmune process, e.g., rheumatoid arthritis) and non-Sjogren's syndrome dry eye (lacrimal dysfunction, but the systemic
  • autoimmune features of Sjogren's syndrome are excluded, e.g., age-related dry eye).
  • the actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
  • An example of a topical heterogeneous ophthalmic solution with its various components (w/w) useful for treating an eye disorder is as follows: brimonidine tartrate in the amount of 0.02% to 0.2% by weight, preferably about 0.075% and cyclosporine 0.01 to 0.1% by weight, surfactant such as Polysorbate 80 at about 0.02% - 2% by weight or poloxamer/tyloxapol at about 0.1% and 0.25% by weight; carbomer copolymer (type A or type B) about 0.05% by weight; tonicity agent (glycerine or includes glycerine about 2.2% by weight; phosphate (combination of dibasic and monobasic) buffer (or other buffers such as Tris or sodium citrate buffer) of pH 6.0 - 8.0; sodium EDTA in the amount of about 0.02% or less by weight; an oil (e.g., castor oil) in the amount of about 1.25% by weight.
  • brimonidine tartrate in the amount of 0.0
  • the oil for the oil phase is a medium chain triglyceride in the range from 0.5 - 4%, typically at about 2%.
  • all water soluble components can be added and heated (about 60-70° C) to make water the phase with buffer.
  • a lipophilic solution is prepared using a lipophilic solvent (e.g., castor oil) and heating to about 60-70° C.
  • Heterogeneous solution is formed by rapid addition of lipophilic solution into water phase followed by high shear mixing.
  • the final solution is sterilized via 0.22 micron filter. Alternatively, sterilization can also be done by autoclaving at about 121° C for 20 min.
  • the sterilized heterogeneous solution is filled into single dose disposable tubes by BFS technology or the like.
  • Another general method for preparing a heterogeneous aqueous solution comprising a composition of the invention is as follows:
  • a topical ophthalmic nanoemulsion formulation with its various components (w/w) useful for treating an eye disorder is as follows: it contains colloid particles with an average particle size of equal to or less than 0.2 pm and greater than 0.02 pm and has an oily core surrounded by an interfacial film.
  • the size population distribution of the colloidal particles may be monomodal.
  • the solution contains anywhere from 0.05% to 0.5% (e.g., 0.2%) alpha 2 adrenergic receptor agonist, cyclosporine from 0.01% to 0.3% (e.g., 0.075%), and 0.5 to 4% w/w (e.g., 1.25% w/w) castor oil or medium chain glycerides. It contains surfactants, preferably 0.5-4% by weight, polysorbate 80 (e.g. about 1.0% by weight); acrylate/Cl0-30 alkyl acrylate cross-polymer (about 0.05% by weight).
  • Topical ophthalmic solution contains a tonicity agent or a demulcent component (e.g., glycerine, which can be in an amount of about 2.2% by weight), a buffer, such sodium citrate, tris-base to adjust the pH.
  • a tonicity agent or a demulcent component e.g., glycerine, which can be in an amount of about 2.2% by weight
  • a buffer such sodium citrate
  • tris-base to adjust the pH.
  • the pH of this topical ophthalmic solution may be in the range of about 6.0 to about 8.0.
  • the topical ophthalmic solution is therapeutically effective in increasing tear production.
  • a topical ophthalmic aqueous solution with its various components (w/w) useful for treating an eye disorder is as follows: it contains colloid particles with an average particle size of equal to or less than 0.2 pm and greater than 0.02 pm and has an oily core surrounded by an interfacial film.
  • the size population distribution of the colloidal particles may be monomodal.
  • the solution contains anywhere from 0.05% to 0.2% (e.g., 0.075%) alpha 2 adrenergic receptor agonist (e.g., brimonidine or a salt thereof) in weight to the total weight (w/w) of the oil phase, cyclosporine from 0.01% to 0.3% (e.g., 0.1%), and 0.5 to 4% w/w (e.g., 2% w/w) medium-chain triglycerides, 0.02% w/w benzalkonium chloride or no benzalkonium (preservative-free) for single dose sterile containers, and surfactants.
  • alpha 2 adrenergic receptor agonist e.g., brimonidine or a salt thereof
  • cyclosporine from 0.01% to 0.3% (e.g., 0.1%)
  • 0.5 to 4% w/w e.g., 2% w/w
  • medium-chain triglycerides 0.02% w/w
  • the surfactants for example, consist of a mixture of tyloxapol in an amount of 0.3% w/w and poloxamer in an amount of 0.1% w/w.
  • the ophthalmic solution can include one or more oils selected from, castor, olive, soy, com, mineral, cottonseed, safflower and sesame.
  • the solution does not contain any significant amount ( ⁇ 1%, typically ⁇ 0.5%, often ⁇ 0.1% and most often ⁇ 0.01%) of substances capable of generating a negative charge and/or phospholipids.
  • the ophthalmic heterogeneous solution can be used for treating a dry eye syndrome.
  • a topical ophthalmic nanoemulsion formulation with its various components (w/w) useful for treating an eye disorder contains brimonidine tartrate in an amount of about 0.2%; lifitegrast from 0.3% to 10% by weight, preferably 4% by weight, polysorbate 80 (e.g. about 1.0% by weight); acrylate/C 10-30 alkyl acrylate cross-polymer (about 0.05% by weight); water q.s.; and castor oil in an amount of about 1.25% by weight.
  • Topical ophthalmic solution contains a tonicity agent or a demulcent component (e.g., glycerine, which can be in an amount of about 2.2% by weight), a buffer, such sodium citrate, tris-base to adjust the pH.
  • a tonicity agent or a demulcent component e.g., glycerine, which can be in an amount of about 2.2% by weight
  • a buffer such sodium citrate
  • tris-base to adjust the pH.
  • the pH of this topical ophthalmic solution may be in the range of about 6.0 to about 8.0.
  • the topical ophthalmic solution is therapeutically effective in increasing tear production.
  • a topical ophthalmic aqueous solution with its various components (w/w) useful for treating an eye disorder contains brimonidine tartrate in an amount of about 0.02%; lifitegrast from 0.3% to 10% by weight, preferably 3% by weight, polysorbate 80 (e.g. about 1.0% by weight); acrylate/C 10-30 alkyl acrylate cross polymer (about 0.05% by weight); water q.s.; and castor oil in an amount of about 1.25% by weight.
  • the alpha 2 adrenergic receptor agonist lifitegrast are the only active agents present in the topical ophthalmic solution but contains a tonicity agent or a demulcent component (e.g., glycerine, which can be in an amount of about 2.2% by weight), a buffer.
  • the pH of this topical ophthalmic solution may be in the range of about 6.0 to about 8.0.
  • the topical ophthalmic solution is therapeutically effective in increasing tear production.
  • w/w is as follows: It contains brimonidine tartrate in an amount ranging from about 0.01% to about 0.5%, typically in an amount of about 0.2% by weight; cyclosporine from 0.01% to about 0.2%, typically in an amount of about 0.075% by weight; lifitegrast from 0.3% to 10% by weight, typically 4% by weight, carbomer homopolymer type B in an amount ranging from about 0.2 to about 0.6%, typically in an amount of about 0.4% or about 0.25%, and/or carbomer homopolymer type C in an amount ranging from about 0.4 to about 5% typically in an amount of about 4% or about 2.5%, and/or polycarbophil in an amount ranging from about 0.2% to about 0.5% typically in an amount of about 0.4% or about 0.2%; glycerin in an amount ranging from about 0.5% to about 1% typically in an amount of about 0.9%; benzalkonium chloride in an amount ranging from about 0.003% to about 0.01% typically in an amount of about
  • the topical ophthalmic solution is therapeutically effective for treating dry eye syndrome.
  • preservatives such as benzalkonium chloride can be used in the formulations of the present invention as described in the non-limiting examples, typically the formulations are preservative-free.
  • brimonidine tartrate in the amount of 0.02% to 0.3% by weight, typically about 0.1 to 0.2% and loteprednol etabonate 0.02 to 0.6% by weight, typically about 0.1 to 0.3%, surfactant such as Polysorbate 80 at about 0.02% - 2% by weight or poloxamer/tyloxapol at about 0.1% and 0.25% by weight; carbomer copolymer (type A or type B) about 0.05% by weight; tonicity agent (glycerine or includes glycerine about 2.2% by weight; sodium citrate and tris buffer of pH 6.0- 8.0, sodium EDTA in the amount of about 0.02% or less by weight; an oil (e.g., castor oil) in the amount of about 1.25% by weight.
  • surfactant such as Polysorbate 80 at about 0.02% - 2% by weight or poloxamer/tyloxapol at about 0.1% and 0.25% by weight
  • carbomer copolymer type A or type B
  • the oil for the oil phase is a medium chain triglyceride in the range from 0.5 - 4%, typically at about 2%.
  • all water soluble components can be added and heated (about 60-70° C).
  • Oil phase the oil (e.g., castor oil) is heated to about 60-70° C.
  • Coarse heterogeneous solution is formed by rapid addition of oil into water phase followed by high shear mixing.
  • the final heterogeneous solution is sterilized via 0.22 micron filter. Alternatively, sterilization can also be done by autoclaving at about 121° C for 20 min.
  • the sterilized heterogeneous solution is filled into single dose disposable tubes by BFS technology or the like.
  • a topical ophthalmic combination formulation with its various components (w/w) useful for treating an eye disorder is as follows: brimonidine tartartrate in the amount of 0.02% to 0.3% by weight, preferably about 0.1 to 0.2% and loteprednol etabonate 0.02 to 0.6% by weight, preferably about 0.1 to 0.3%, povidone at about 0.6% by weight, poloxamer/tyloxapol at about 0.1% and 0.25% by weight; tonicity agent (glycerine or includes glycerine about 1 to 3% by weight; sodium citrate and tris buffer of pH 6.0 - 8.0; sodium EDTA in the amount of about 0.02% or less by weight.
  • brimonidine tartartrate in the amount of 0.02% to 0.3% by weight, preferably about 0.1 to 0.2% and loteprednol etabonate 0.02 to 0.6% by weight, preferably about 0.1 to 0.3%, povidone at about 0.6% by weight, poloxamer/tyloxa
  • Ophthalmic pharmaceutical compositions can be formulated with the compositions shown in Table below.
  • Heterogeneous solution formulation can be prepared according to the process described below where the water insoluble active(s) are added to the oil phase (e.g., castor oil) before introducing the oil phase to the aqueous phase.
  • oil phase e.g., castor oil
  • Oil phase Mix appropriate amounts of castor oil and polysorbate 80 until uniformity is obtained;
  • Aqueous phase Mix required amounts of Pemulen, water and glycerin until
  • formulations containing different combinations of active ingredients are: bromonidine or brimonidine tartrate + cyclosporine; bromonidine or brimonidine tartrate + lifitegrast; cyclosporine + lifitegrast combination; bromonidine or brimonidine tartrate + cyclosporine + lifitegrast; brimonidine or brimonidine tartrate + loteprednol etabonate, etc.
  • heterogeneous solutions are allowed to stand for a period of time (e.g., 6 months) at 20 to 25 °C, and the heterogeneity sizes are measured.
  • the heterogeneity sizes within a period of time e.g., 6 months
  • Aqueous formulation (homogeneous and heterogeneous solutions): General process for producing aqueous formulation of the compositions of the invention is provided below. Briefly, for X Volume (V) of final formulation - complete following steps:
  • Combined Aqueous Formulations Example of combination product of aqueous formulation of Brimonidine Tartrate and Liftegrast:
  • Treatment Example Several drops of a given formulation exemplified herein are administered to the eye(s) of a patient suffering from dry eye syndrome. Reduction of the symptoms becomes noticeable within a reasonable period. The treatment is repeated one or more times daily while the condition persists.
  • Combination Formulation Various combinations of active pharmaceutical ingredient combinations were prepared using the processes disclosed herein.
  • the particle or globule size distribution of these exemplary ophthalmic nanoemulsion formulations were determined using particle size analyzer, Mastersizer 3000TM (Malvern Panalytical, Malvern, UK).
  • Formulations were dispersed in water during measurement and data were plotted as volume density (%) of particle v. size.
  • Median size of globules/particles in formulation reported as Dx (50) as presented in tables in Figures 1-3.
  • the physical stability nanoemulsion/solution/suspension formulations were also monitored using size distribution analysis over the extended time at various temperatures. For example, formulations are incubated for a period (e.g., 1-3 months) at storage temperature (e.g., 20 °C to 25 °C), and accelerated (e.g., 40 °C), and harsh (e.g., 60 °C) and the heterogeneity in sizes were measured.
  • the heterogeneity in sizes, within experimental error, should be identical at end of the test period to those measured right after the nanoemulsion/suspension/solutions were prepared. Such consistency in the particle size would indicate that there is no significant coalescence of the heterogeneity at storage temperature. Even under accelerated stability temperature, there was no significant change in median size of globule/particles ( Figures 2 and 3).
  • the quantity of active pharmaceutical ingredients in various exemplary nanoemulsion formulations were determined using RP-HPLC methods.
  • HPLC method utilized a mixture of acetonitrile and a low pH buffer as an eluent.
  • the chemical stability of APIs in nanoemulsion/solution/suspension formulations was determined using HPLC method after incubation for an extended time at various temperatures.
  • formulations are incubated at storage temperature (e.g., 20 to 25 °C), and accelerated (e.g., 40 °C), and harsh (e.g., 60 °C) and the purity was measured using HPLC method.
  • storage temperature e.g. 20 to 25 °C
  • accelerated e.g., 40 °C
  • harsh e.g. 60 °C
  • the purity was substantially identical at the end of the 2 week test period compares to those measured right after the nanoemulsion formulation (Figure 5) thereby suggesting that there is no significant degradation at storage temperature, accelerated and even at harsh temperature.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Emergency Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP19856338.9A 2018-08-29 2019-08-29 Ophthalmische zusammensetzungen und verfahren zur verwendung Withdrawn EP3843721A4 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16/116,872 US20190008920A1 (en) 2017-05-19 2018-08-29 Ophthalmic compositions and methods of use
PCT/US2019/048721 WO2020047197A1 (en) 2018-08-29 2019-08-29 Ophthalmic compositions and methods of use

Publications (2)

Publication Number Publication Date
EP3843721A1 true EP3843721A1 (de) 2021-07-07
EP3843721A4 EP3843721A4 (de) 2022-10-12

Family

ID=69644699

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19856338.9A Withdrawn EP3843721A4 (de) 2018-08-29 2019-08-29 Ophthalmische zusammensetzungen und verfahren zur verwendung

Country Status (3)

Country Link
EP (1) EP3843721A4 (de)
CN (1) CN111212642A (de)
WO (1) WO2020047197A1 (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024042550A1 (en) * 2022-08-25 2024-02-29 Sentiss Pharma Private Limited Ophthalmic combination composition
CN120960148B (zh) * 2025-09-15 2026-04-10 安徽辰旭视光科技有限公司 一种用于治疗免疫性干眼症的眼用纳米乳制剂及其制备方法

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2094688B1 (es) * 1994-08-08 1997-08-01 Cusi Lab Manoemulsion del tipo de aceite en agua, util como vehiculo oftalmico y procedimiento para su preparacion.
AU1731101A (en) * 1999-12-07 2001-06-18 Rohto Pharmaceutical Co., Ltd. Ophthalmic compositions
AU2005304035B2 (en) * 2004-11-09 2010-07-22 Santen Sas Ophthalmic oil-in-water type emulsion with stable positive zeta potential
JP2009514969A (ja) * 2005-11-09 2009-04-09 コンビナトアールエックス インコーポレーティッド 医学的状態を治療するための方法、組成物、およびキット
MX2007010025A (es) * 2007-08-17 2009-02-25 Arturo Jimenez Bayardo Composición farmacéutica para tratamiento de hipertensión ocular.
US9034830B2 (en) * 2009-10-30 2015-05-19 Intratus, Inc. Methods and compositions for sustained delivery of drugs
AU2012351948A1 (en) * 2011-12-16 2014-07-10 Allergan, Inc. Ophthalmic compositions comprising polyvinyl capralactam - polyvinyl acetate - polyethylene glycol graft copolymer
EP2664329A1 (de) * 2012-05-15 2013-11-20 F. Holzer GmbH Ophthalmologisches Vehikelsystem
CN102895245A (zh) * 2012-10-30 2013-01-30 河南牧翔动物药业有限公司 一种复方甲氧苄啶与盐酸多西环素纳米乳制剂及其制备方法
US20170239331A1 (en) * 2014-10-15 2017-08-24 Rapid Pathogen Screening, Inc. Formulations for histatin protectives and therapeutics
EP3209331B1 (de) * 2014-10-20 2023-07-12 Sentiss Pharma Private Limited Augenlösung
US10751337B2 (en) * 2015-02-24 2020-08-25 Ocugen, Inc. Preservative free ocular compositions and methods for using the same for treating dry eye disease and other eye disorders
MX2017010544A (es) * 2015-02-24 2018-06-18 Univ Illinois Metodos y composiciones para tratar la enfermedad del ojo seco y otros trastornos del ojo.
US20180221278A1 (en) * 2015-02-24 2018-08-09 Ocugen, Inc. Prsustained release opthalmic formuation and methods for using the same
US9981041B2 (en) * 2016-08-23 2018-05-29 Ira Jason Salzman Ophthalmic lubricating spray
US11510931B2 (en) * 2016-09-28 2022-11-29 Medicon Pharmaceuticals, Inc. Compositions and methods for treating ophthalmic conditions
KR20190124704A (ko) * 2017-01-24 2019-11-05 마크레젠, 인크. 아포지질단백질 모방체를 이용하는, 나이 관련 황반 변성 및 기타 안질환의 치료

Also Published As

Publication number Publication date
EP3843721A4 (de) 2022-10-12
CA3115664A1 (en) 2020-03-05
WO2020047197A1 (en) 2020-03-05
CN111212642A (zh) 2020-05-29

Similar Documents

Publication Publication Date Title
US10555947B2 (en) Ophthalmic compositions and methods of use
US20190008920A1 (en) Ophthalmic compositions and methods of use
EP3261620B1 (de) Verfahren und zusammensetzungen zur behandlung von trockenem auge und anderen augenerkrankungen
US11759472B2 (en) Compositions and methods of use for treating aberrant inflammation in peri-ocular secretory glands or at the ocular surface
WO2021124301A1 (en) Formulations and method for treatment of inflammatory diseases
JP2017531045A (ja) 眼科用液剤
JP7796783B2 (ja) 眼周囲分泌腺におけるまたは眼表面での異常な炎症を処置するための組成物および使用方法
EP3843721A1 (de) Ophthalmische zusammensetzungen und verfahren zur verwendung
US20200206137A1 (en) Microparticle formulations for delivery of active agents
EP3787611A1 (de) Flüssiges depot zur nichtinvasiven verzögerten verabreichung von wirkstoffen an das auge
WO2021240376A2 (en) Ophthalmic nanoemulsion compositions
CA3115664C (en) Ophthalmic compositions and methods of use
WO2020240451A1 (en) In-situ gelling nanoemulsion of brinzolamide
US20180333357A1 (en) Nanoemulsions with anti-inflammatory activity
US20180221278A1 (en) Prsustained release opthalmic formuation and methods for using the same
WO2023152644A1 (en) Pharmaceutical composition of lifitegrast and loteprednol etabonate
US9877964B2 (en) Methods and compositions for treating dry eye disease and other eye disorders
OA19529A (en) Compositions and methods for treating aberrant inflammation in peri - ocular secretory glands or at the ocular surface.

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20210329

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 27/02 20060101ALI20220602BHEP

Ipc: A61K 9/107 20060101ALI20220602BHEP

Ipc: A61K 31/436 20060101ALI20220602BHEP

Ipc: A61K 31/56 20060101ALI20220602BHEP

Ipc: A61K 31/4725 20060101ALI20220602BHEP

Ipc: A61K 38/13 20060101ALI20220602BHEP

Ipc: A61K 31/498 20060101ALI20220602BHEP

Ipc: A61K 31/137 20060101ALI20220602BHEP

Ipc: A61K 47/32 20060101ALI20220602BHEP

Ipc: A61K 47/18 20170101ALI20220602BHEP

Ipc: A61K 47/12 20060101ALI20220602BHEP

Ipc: A61K 47/10 20170101ALI20220602BHEP

Ipc: A61K 47/26 20060101ALI20220602BHEP

Ipc: A61K 47/44 20170101ALI20220602BHEP

Ipc: A61K 31/573 20060101ALI20220602BHEP

Ipc: A61K 31/407 20060101ALI20220602BHEP

Ipc: A61K 9/08 20060101ALI20220602BHEP

Ipc: A61K 9/00 20060101ALI20220602BHEP

Ipc: A61K 31/417 20060101AFI20220602BHEP

A4 Supplementary search report drawn up and despatched

Effective date: 20220913

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 27/02 20060101ALI20220907BHEP

Ipc: A61K 9/107 20060101ALI20220907BHEP

Ipc: A61K 31/436 20060101ALI20220907BHEP

Ipc: A61K 31/56 20060101ALI20220907BHEP

Ipc: A61K 31/4725 20060101ALI20220907BHEP

Ipc: A61K 38/13 20060101ALI20220907BHEP

Ipc: A61K 31/498 20060101ALI20220907BHEP

Ipc: A61K 31/137 20060101ALI20220907BHEP

Ipc: A61K 47/32 20060101ALI20220907BHEP

Ipc: A61K 47/18 20170101ALI20220907BHEP

Ipc: A61K 47/12 20060101ALI20220907BHEP

Ipc: A61K 47/10 20170101ALI20220907BHEP

Ipc: A61K 47/26 20060101ALI20220907BHEP

Ipc: A61K 47/44 20170101ALI20220907BHEP

Ipc: A61K 31/573 20060101ALI20220907BHEP

Ipc: A61K 31/407 20060101ALI20220907BHEP

Ipc: A61K 9/08 20060101ALI20220907BHEP

Ipc: A61K 9/00 20060101ALI20220907BHEP

Ipc: A61K 31/417 20060101AFI20220907BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20230412