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WO2018193367A1 - Novel pharmaceutical composition comprising combination of alcaftadine and nepafenac along with antibacterial and/or antiviral an/or antifungal drug - Google Patents

Novel pharmaceutical composition comprising combination of alcaftadine and nepafenac along with antibacterial and/or antiviral an/or antifungal drug Download PDF

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Publication number
WO2018193367A1
WO2018193367A1 PCT/IB2018/052647 IB2018052647W WO2018193367A1 WO 2018193367 A1 WO2018193367 A1 WO 2018193367A1 IB 2018052647 W IB2018052647 W IB 2018052647W WO 2018193367 A1 WO2018193367 A1 WO 2018193367A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
nepafenac
alcaftadine
composition according
drug
Prior art date
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Ceased
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PCT/IB2018/052647
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French (fr)
Inventor
Sivakumar Venkata BOBBA
Bhimrao Jadhav
Dhananjay Shinde
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Zenvision Pharma LLP
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Zenvision Pharma LLP
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Publication of WO2018193367A1 publication Critical patent/WO2018193367A1/en
Anticipated expiration legal-status Critical
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    • 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
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention relates to novel pharmaceutical composition
  • novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug for the treatment of ophthalmic disorder.
  • Eyes are the critical sensory organ of the human being. Eyes provide organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Most people have eye problems at one time or another. Some are minor and will go away on their own, or are easy to treat at home. Others need a specialist's care. The ophthalmic disorder or abnormalities of the eyes are associated with allergies, inflammation, infection; to counteract the same role of antihistamine, NSAID (Non-steroidal antiinflammatory drug), antibacterial, antifungal and antiviral drugs is very vital.
  • NSAID Non-steroidal antiinflammatory drug
  • Anti-histaminic drug such as Alcaftadine is a H1 histamine receptor antagonist. Chemically Alcaftadine is 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H- imidazo[2,1-b] [3] benzazepine-3-carboxaldehyde and its molecular weight is 307.39. Its empirical formula is C 19 ⁇ 21 ⁇ 3 ⁇ . Alcaftadine is represented by compound of structural formula I.
  • Alcaftadine is white to yellow powder with slight solubility in water.
  • Alcaftadine ophthalmic solution has been approved in USA as on Jul 28, 2010 under the trade name Lastacifand is available in the strength of 0.25%.
  • Nepafenac is a non-steroidal anti-inflammatory prodrug. Chemically Nepafenac is 2-amino-3-benzoylbenzeneacetamide and its molecular weight is 254.28. Its empirical formula is C 15 H 14 N 2 O 2 . Nepafenac is represented by compound of structural formula II.
  • Nepafenac is a yellow crystalline powder and practically insoluble in water.
  • Nepafenac ophthalmic suspension has been approved in USA as on Aug 19, 2005 under the trade name Nevan3 ⁇ 4and is available in the strength of 0.1 %. Also the Nepafenac ophthalmic suspension has been approved in USA as on Oct 16, 2012 under the trade name llevro® and is available in the strength of 0.3%.
  • Ocular infections may be bacterial or viral or fungal.
  • Several antibacterial, antiviral and antifungal agents are used to treat Ocular infections caused by bacteria or virus or fungi.
  • U.S. Patent Publication No. 20130281506 discloses generically composition comprising a combination of a non-steroidal anti-inflammatory drug with an antihistamine drug intended for an ophthalmic use.
  • This patent publication particularly related to combination of ketorolac (non-steroidal anti-inflammatory drug) with olopatadine (anti- histaminic drug) for the treatment of seasonal ocular surface allergy.
  • U.S. Patent Publication No. 20140206708 discloses generically combination of antihistamine, NSAID, antibiotic, antiviral drugs for ophthalmic disorder; however, this patent publication number does not disclose or teaches combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral drug and/or antifungal drug.
  • Florida Administrative code and Florida administrative register, section 64B13-18.002 Formulary of Topical Ocular Pharmaceutical Agents discloses generically "alone or combination of cycloplegic and mydriatics, local anesthetics, diagnostic products, antibacterial, NSAID, antihistamines, antiviral, antifungal and anti-glaucoma agents for the ophthalmic disorder".
  • Nepafenac ophthalmic suspension suffers from several adverse effects such as capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, sticky sensation, conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing, vitreous detachment, headache, hypertension, nausea/vomiting and sinusitis.
  • the commercially available alcaftadine ophthalmic solution shows several adverse effects such as eye irritation, burning and/or stinging on instillation, eye redness, eye pruritus, eye discharge, eye swelling, erythema of eyelid, eyelid edema, increased lacrimation, blurred vision, nasopharyngitis, headache, hypersensitivity reactions including swelling of the face or allergic dermatitis and somnolence.
  • Eyes are the critical sensory organ of the human being and are associated with several ophthalmic disorders. The eyes are also susceptible to bacterial, viral and fungal infection.
  • the commercially available product and product known in the prior art for Nepafenac, Alcaftadine, antibacterial or antiviral or antifungal drugs shows several adverse effects such as capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, sticky sensation, conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing, vitreous detachment, headache, hypertension, nausea/vomiting, sinusitis, eye irritation, burning, eye redness, eye discharge, eye swelling, erythema of eyelid, increased lacrimation blurred vision, nasopharyngitis, hypersensitivity reactions including swelling of the face or allergic dermatitis and somnolence. Also the commercially available product and product known in the prior art are not efficacious and does not provide patient compliance in the treatment of ophthalmic disorder.
  • novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug. It is another object of the present invention to provide novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug which is efficacious in the treatment of ophthalmic disorder.
  • It is another object of the present invention to provide novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug with less adverse effects in the treatment of ophthalmic disorder.
  • It is another object of the present invention to provide novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug which provides patient compliance in the treatment of ophthalmic disorder.
  • a first aspect of the present invention is to provide novel pharmaceutical combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug in the treatment of ophthalmic disorders.
  • novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug in the treatment of ophthalmic disorders.
  • novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug in the treatment of ophthalmic disorders; particularly associated with bacterial or viral or fungal infection.
  • in another aspect of the present invention is to provide novel pharmaceutical composition comprising combination of Alcaftadine, Nepafenac along with antibacterial and/or antiviral and/or antifungal drug and pharmaceutically acceptable excipients in the treatment of ophthalmic disorders.
  • In another aspect of the present invention is to provide process of preparing novel pharmaceutical composition comprising combination of Alcaftadine, Nepafenac along with antibacterial and/or antiviral and/or antifungal drug and pharmaceutically acceptable excipients in the treatment of ophthalmic disorders.
  • the present invention relates to novel pharmaceutical combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug in the treatment of ophthalmic disorders.
  • the ophthalmic disorder may be the any abnormality associated with eye.
  • the ophthalmic disorders in the present invention may be selected from but not limited to Blepharitis, Blepharoconjunctivitis, Cytomegalovirus retinitis, Conjunctivitis, Corneal Ulcer, Herpes Simplex Dendritic Keratitis, Herpetic Keratitis, Hordeolum, Keratitis, Keratoconjunctivitis, Neonatal Conjunctivitis, Ophthalmic Surgery, Trachoma, Nearsightedness (myopia), Farsightedness, Astigmatism, Presbyopia, Foreign object in the eye, Cataract, Eye floaters, Corneal abrasion, Eye redness, Dry eyes, Visual disturbances, External eyelid stye, Watery eyes, Eye pain, entropion, Eye burning accompanied by itching and discharge, Eyelid twitch, Glaucoma, Dry eye syndrome, Black eye, Subconjunctival hemmorhage,
  • the anti-histaminic drug alcaftadine provide their primary action by blocking histamine at H1 receptor site. They have no effect on rate of histamine release, nor do they inactivate histamine. By inhibiting the activity of histamine, they are able to treat the ophthalmic disorders.
  • the non-steroidal anti-inflammatory drugs Nepafenac for treating ophthalmic disorders provide their action by inhibiting the activity of Cyclooxygenase, an enzyme required for prostaglandin synthesis.
  • the antibacterial drugs for treating ophthalmic disorders either kill or inhibit the spread of bacteria.
  • the suitable antibacterial drugs of the present invention may be selected from but not limited to gentamicin, tobramycin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, norfloxacin, lomefloxacin, finafloxacin, trovafloxacin, fusidic acid, silver nitrate, enoxacin azithromycin, erythromycin, amikacin, streptomycin, netilmycin, kanamycin, bacitracin, polymyxin B, neomycin, paramomycin, vancomycin, doxycycline, tetracyclines, rifampin, trimethoprim, sulfacetamide, chloramphenicol, cycloserine, ceftriaxone, co-amoxiclav.
  • antibacterial may be
  • the antiviral drugs for treating ophthalmic disorders inhibit viral replication.
  • the suitable antiviral drugs of the present invention may be selected from but not limited to ganciclovir, aciclovir, famciclovir, valaciclovir, trifluorothymidine, idoxuridine, penciclovir, vidarabine, cytarabine, bromo vinyl deoxyuridine, interferons, foscarnet, zidovudine, sorivudine, adenosine arabinoside.
  • antiviral may be ganciclovir.
  • the antifungal drugs for treating ophthalmic disorders either kill or inhibit the spread of fungi.
  • the suitable antifungal drugs of the present invention may be selected from but not limited to natamycin, clotrimazole, amorolfine, amphotericin B, anidulafungin, butoconazole, butenafine, caspofungin, ciclopirox olamine, econazole, fluconazole, flucytosine, griseofulvin, haloprogin, itraconazole, ketoconazole, micafungin, miconazole, miconazole nitrate, naftifine, nikkomycin Z, topical nystatin, liposomal nystatin, oxiconazole, posaconazole, pimaricin, ravuconazole, sulconazole, terbinafine, terconazole, tioconazole, tolnaftate, undecylenate,
  • antifungal may be natamycin.
  • the novel pharmaceutical combination according to present invention effectively treats ophthalmic disorders; wherein Alcaftadine which acts by blocking histamine at H1 receptor site; Nepafenac which acts by inhibiting the activity of cyclooxygenase; antibacterial/antifungal drugs which kill or inhibit the spread of bacteria/fungi, antiviral drugs which inhibits viral replication.
  • concentrations in the novel pharmaceutical combination of Alcaftadine, Nepafenac and antibacterial and/or antiviral and/or antifungal drug has been optimized; so that it provides maximum therapeutic effect with reduction in side effects in the treatment of ophthalmic disorders.
  • the pharmaceutical composition according to present invention may contain any suitable amount of Alcaftadine, Nepafenac, antibacterial preferably Tobramycin and/or antiviral preferably Ganciclovir and/or antifungal preferably Natamycin drug by weight of the composition.
  • the concentration of Alcaftadine may ranges from about 0.0025% to 15% by weight of composition; preferably may ranges from about 0.005% to 1%; more preferably may ranges from about 0.05% to about 0.5%.
  • the concentration of Alcaftadine may be 0.1 %, 0.15%, 0.2%, 0.25%, 0.3%, 0.35% and 0.4%.
  • the concentration of Nepafenac may range from about 0.05% to 2% by weight of composition; preferably may ranges from 0.05% to 1 %; more preferably may ranges from about 0.05% to 0.5%.
  • the concentration of Nepafenac may be 0.075%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, and 0.5%.
  • the concentration of Tobramycin may range from about 0.05% to 5% by weight of composition; preferably may ranges from about 0.01% to 1%; more preferably may ranges from about 0.1 % to about 0.5%.
  • the concentration of Tobramycin may be 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45% and 0.5%.
  • the concentration of Ganciclovir may range from about 0.005% to 5% by weight of composition; preferably may ranges from about 0.05% to 2.5%; more preferably may ranges from about 0.01% to about 1%.
  • the concentration of Ganciclovir may be 0.01 %, 0.05%, 0.075%, 0.1 %, 0.15%, 0.2%, 0.25, 0.3%%, 0.4%, 0.5%, 0.75% and 1%.
  • the concentration of Natamycin may ranges from about 0.05% to 20% by weight of composition; preferably may ranges from about 0.1 % to 15%; more preferably may ranges from about 1 % to about 10%.
  • the concentration of Natamycin may be 0.1%, 1 %, 2%, 2.5%, 3%, 5%, 7%, 7.5%, 8%, 9% and 10%.
  • novel pharmaceutical combination of Alcaftadine, Nepafenac and antibacterial and/or antiviral and/or antifungal drug for the treatment of ophthalmic disorder provides maximum therapeutic effect with no side effects or reduction in side effects like capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, sticky sensation, conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing, vitreous detachment, headache, hypertension, nausea/vomiting, sinusitis, eye irritation, burning, eye redness, eye discharge, eye swelling, erythema of eyelid, increased lacrimation, blurred vision, nasopharyngitis, hypersensitivity reactions including swelling of the face or allergic dermatitis and somnolence.
  • novel pharmaceutical composition comprising combination of Alcaftadine and Nepaf
  • novel pharmaceutical combination of alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug of the present invention may be in the form of ophthalmic composition.
  • novel pharmaceutical ophthalmic composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug for the treatment of ophthalmic disorders may be in the form of eye drop, solution, suspension, microemulsions, ointments, lotions, gels, injections, nanoparticles, liposomes, niosomes, hydrogels and like.
  • the novel pharmaceutical ophthalmic composition comprising combination of Alcaftadine, Nepafenac along with antibacterial and/or antiviral and/or antifungal drug and pharmaceutically acceptable excipient.
  • the novel pharmaceutical ophthalmic composition comprising combination of Alcaftadine, Nepafenac along with antibacterial and/or anti-viral and/or antifungal drug of the present invention may contain one or more excipient selected from the group consisting of solubilizers, buffering agents, tonicity agents, viscosity enhancers, preservatives, antioxidants, pH regulators, chelating agents, surfactants and vehicles.
  • solubilizers include but not limited to polyethylene glycol, propylene glycol, polyoxyethylene monostearate, polyoxyethylene hydrogenated castor oil, polysorbate 80, cyclodextrin or combination thereof.
  • the amount of solubilizers present in the composition may ranges from about 0.1 to 40%; preferably about 1 to 20%; more preferably about 2 to 8%.
  • buffering agents include but not limited to carbonate buffers, borate buffers, phosphate buffers, acetate buffers, citrates, gluconates, lactates, propionates and tromethamine buffers or combination thereof. The amount of buffer adjusted to achieve desired performance properties for the aqueous ophthalmic solution.
  • tonicity agents include but not limited to, mannitol, sorbitol, glycerin, sodium chloride and other electrolytes or combination thereof.
  • the amount of tonicity agents present in the composition may ranges from about 0.01 % (w/v) to about 7% by weight of composition.
  • viscosity enhancers include but not limited to carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, chondroitin sulfate or combination thereof.
  • the viscosity enhancers present in an amount less than about 10% by weight of the composition.
  • preservatives include but not limited to benzalkonium chloride, benzethonium chloride, parahydroxybenzoic acid esters, cetyl pyridinium chloride, sodium dehydroacetate, phenylethyl alcohol, chlorobutanol, phenylmercuric acetate, phenylmercuric nitrate or combination thereof.
  • the amount of preservative present in the composition may ranges from about 0.001-0.05% by weight of composition; preferably about 0.005 to 0.030%; more preferably about 0.01 to 0.025%.
  • antioxidants include but not limited to Sodium bisulfite, Sodium metabisulfite, Ethylenediaminetetraacetic acid, Thiourea or combination thereof.
  • pH regulators include but not limited to citric acid, acetic acid, hydrochloric acid, phosphoric acid, sodium carbonate, sodium hydroxide, potassium hydroxide or combination thereof.
  • the compositions of the present invention have a pH ranges from 4-9. Preferably, the pH of the compositions is 6.5-8.
  • chelating agents include but not limited to EDTA and its salts.
  • the amount of chelating agents present in the composition may ranges from about 0.001-2% by weight of composition.
  • surfactants include but not limited to propylene glycol, tyloxapol, poloxamers, sorbitan esters, polyoxyl stearates, polysorbates, polyoxyethylene castor oil derivatives, caprylocaproyl polyoxyl-8 glycerides or combination thereof.
  • the amount of surfactant present in the composition may ranges from about 0.1 to 40% by weight of composition; preferably about 1 % to 20%; more preferably 2 to 8%.
  • vehicle examples include but not limited to sterile purified water, propylene glycol, oils such as olive oil, castor oil, sesame oil or combination thereof.
  • In another aspect of the present invention is to provide process of preparing novel pharmaceutical composition comprising combination of Alcaftadine, Nepafenac along with antibacterial and/or antiviral and/or antifungal drug and pharmaceutically acceptable excipients in the treatment of ophthalmic disorders.
  • the process of manufacturing ophthalmic composition according to present invention involves mixing Nepafenac and Alcaftadine with either antibacterial or antiviral or antifungal agent along with one or more pharmaceutically acceptable excipients like solubilizers, buffering agents, tonicity agents, viscosity enhancers, preservatives, antioxidants, pH regulators, chelating agents, surfactants and vehicles; and filtering the resulting solution through micron filter.
  • the ophthalmic compositions according to present invention were evaluated for appearance, assay, pH, osmolarity, particulates foreign matter, sterility and found to be within the specifications.
  • novel pharmaceutical ophthalmic composition of the present invention may be filled in to the single dose container or multiple dose containers and packaged into the plastic or glass containers.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
  • Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Caprylocaproyl polyoxyl-8 glycerides.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
  • Benzalkonium chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Caprylocaproyl polyoxyl-8 glycerides.
  • Step 4 Solution of Step: 1 was added to mixture of Step : 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
  • Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Caprylocaproyl polyoxyl-8 glycerides.
  • Step :1 Solution of Step :1 was added to mixture of Step : 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
  • Step 4 Solution of Step: 1 was added to mixture of Step : 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
  • Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Polysorbate.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
  • Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Polysorbate.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
  • Benzalkonium chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Polysorbate.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
  • Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Polysorbate.
  • Step 4 Solution of Step: 1 was added to mixture of Step : 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
  • Benzalkonium chloride, Alcaftadine and Natamycin were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Polysorbate. Solution of Step: 1 was added to mixture of Step: 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
  • Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
  • Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.

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Abstract

The present disclosure relates to novel pharmaceutical composition comprising Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug in the treatment of ophthalmic disorders which counteracts the allergies, inflammation and infection associated with eye.

Description

NOVEL PHARMACEUTICAL COMPOSITION COMPRISING COMBINATION
OF ALCAFTADINE AND NEPAFENAC ALONG WITH ANTIBACTERIAL AND/OR ANTIVIRAL AND/OR ANTIFUNGAL DRUG FIELD OF THE INVENTION
The present invention relates to novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug for the treatment of ophthalmic disorder. BACKGROUND OF THE INVENTION
Eyes are the critical sensory organ of the human being. Eyes provide organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Most people have eye problems at one time or another. Some are minor and will go away on their own, or are easy to treat at home. Others need a specialist's care. The ophthalmic disorder or abnormalities of the eyes are associated with allergies, inflammation, infection; to counteract the same role of antihistamine, NSAID (Non-steroidal antiinflammatory drug), antibacterial, antifungal and antiviral drugs is very vital.
Anti-histaminic drug such as Alcaftadine is a H1 histamine receptor antagonist. Chemically Alcaftadine is 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H- imidazo[2,1-b] [3] benzazepine-3-carboxaldehyde and its molecular weight is 307.39. Its empirical formula is C19Η21Ν3Ο. Alcaftadine is represented by compound of structural formula I.
Figure imgf000003_0001
Alcaftadine is white to yellow powder with slight solubility in water.
Alcaftadine ophthalmic solution has been approved in USA as on Jul 28, 2010 under the trade name Lastacifand is available in the strength of 0.25%.
NSAID's such as Nepafenac is a non-steroidal anti-inflammatory prodrug. Chemically Nepafenac is 2-amino-3-benzoylbenzeneacetamide and its molecular weight is 254.28. Its empirical formula is C15H14N2O2. Nepafenac is represented by compound of structural formula II.
Figure imgf000003_0002
Nepafenac is a yellow crystalline powder and practically insoluble in water.
Nepafenac ophthalmic suspension has been approved in USA as on Aug 19, 2005 under the trade name Nevan¾and is available in the strength of 0.1 %. Also the Nepafenac ophthalmic suspension has been approved in USA as on Oct 16, 2012 under the trade name llevro® and is available in the strength of 0.3%.
Ocular infections may be bacterial or viral or fungal. Several antibacterial, antiviral and antifungal agents are used to treat Ocular infections caused by bacteria or virus or fungi. U.S. Patent Publication No. 20130281506 discloses generically composition comprising a combination of a non-steroidal anti-inflammatory drug with an antihistamine drug intended for an ophthalmic use. This patent publication particularly related to combination of ketorolac (non-steroidal anti-inflammatory drug) with olopatadine (anti- histaminic drug) for the treatment of seasonal ocular surface allergy.
U.S. Patent Publication No. 20140206708 discloses generically combination of antihistamine, NSAID, antibiotic, antiviral drugs for ophthalmic disorder; however, this patent publication number does not disclose or teaches combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral drug and/or antifungal drug.
Florida Administrative code and Florida administrative register, section 64B13-18.002 Formulary of Topical Ocular Pharmaceutical Agents discloses generically "alone or combination of cycloplegic and mydriatics, local anesthetics, diagnostic products, antibacterial, NSAID, antihistamines, antiviral, antifungal and anti-glaucoma agents for the ophthalmic disorder".
Nepafenac ophthalmic suspension i.e. both has been used for the
Figure imgf000004_0001
treatment of pain and inflammation associated with cataract surgery.
Alcaftadine ophthalmic solution i.e. Lastac®alftas been used for the prevention of itching associated with allergic conjunctivitis. The commercially available Nepafenac ophthalmic suspension suffers from several adverse effects such as capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, sticky sensation, conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing, vitreous detachment, headache, hypertension, nausea/vomiting and sinusitis. The commercially available alcaftadine ophthalmic solution shows several adverse effects such as eye irritation, burning and/or stinging on instillation, eye redness, eye pruritus, eye discharge, eye swelling, erythema of eyelid, eyelid edema, increased lacrimation, blurred vision, nasopharyngitis, headache, hypersensitivity reactions including swelling of the face or allergic dermatitis and somnolence.
Eyes are the critical sensory organ of the human being and are associated with several ophthalmic disorders. The eyes are also susceptible to bacterial, viral and fungal infection.
The commercially available product and product known in the prior art for Nepafenac, Alcaftadine, antibacterial or antiviral or antifungal drugs shows several adverse effects such as capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, sticky sensation, conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing, vitreous detachment, headache, hypertension, nausea/vomiting, sinusitis, eye irritation, burning, eye redness, eye discharge, eye swelling, erythema of eyelid, increased lacrimation blurred vision, nasopharyngitis, hypersensitivity reactions including swelling of the face or allergic dermatitis and somnolence. Also the commercially available product and product known in the prior art are not efficacious and does not provide patient compliance in the treatment of ophthalmic disorder.
Thus, there is an unmet need in the art to provide novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug in the treatment of ophthalmic disorder.
OBJECTS OF THE INVENTION
Accordingly, it is an object of the present invention to provide novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug. It is another object of the present invention to provide novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug which is efficacious in the treatment of ophthalmic disorder.
It is another object of the present invention to provide novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug with less adverse effects in the treatment of ophthalmic disorder.
It is another object of the present invention to provide novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug which provides patient compliance in the treatment of ophthalmic disorder.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide novel pharmaceutical combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug in the treatment of ophthalmic disorders.
In another aspect of the present invention is to provide novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug in the treatment of ophthalmic disorders. In another aspect of the present invention is to provide novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug in the treatment of ophthalmic disorders; particularly associated with bacterial or viral or fungal infection. In another aspect of the present invention is to provide novel pharmaceutical composition comprising combination of Alcaftadine, Nepafenac along with antibacterial and/or antiviral and/or antifungal drug and pharmaceutically acceptable excipients in the treatment of ophthalmic disorders.
In another aspect of the present invention is to provide process of preparing novel pharmaceutical composition comprising combination of Alcaftadine, Nepafenac along with antibacterial and/or antiviral and/or antifungal drug and pharmaceutically acceptable excipients in the treatment of ophthalmic disorders.
DETAIL DESCRIPTION OF THE INVENTION
The present invention relates to novel pharmaceutical combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug in the treatment of ophthalmic disorders.
The ophthalmic disorder may be the any abnormality associated with eye. The ophthalmic disorders in the present invention may be selected from but not limited to Blepharitis, Blepharoconjunctivitis, Cytomegalovirus retinitis, Conjunctivitis, Corneal Ulcer, Herpes Simplex Dendritic Keratitis, Herpetic Keratitis, Hordeolum, Keratitis, Keratoconjunctivitis, Neonatal Conjunctivitis, Ophthalmic Surgery, Trachoma, Nearsightedness (myopia), Farsightedness, Astigmatism, Presbyopia, Foreign object in the eye, Cataract, Eye floaters, Corneal abrasion, Eye redness, Dry eyes, Visual disturbances, External eyelid stye, Watery eyes, Eye pain, entropion, Eye burning accompanied by itching and discharge, Eyelid twitch, Glaucoma, Dry eye syndrome, Black eye, Subconjunctival hemmorhage, Retinal detachment, Lazy eye, Pterygium, Diabetic retinopathy, Night blindness, Eye emergencies, Visual impairment, Hypertensive retinopathy, Strabismus, Age related macular degeneration, Bulging eyes, Uveitis, Scleritis, Photophobia, Hyphema, Ophthalmoplegia, Ocular migraines, Sarcoidosis, Retinal vascular occlusion, Optic neuritis.
The anti-histaminic drug alcaftadine provide their primary action by blocking histamine at H1 receptor site. They have no effect on rate of histamine release, nor do they inactivate histamine. By inhibiting the activity of histamine, they are able to treat the ophthalmic disorders. The non-steroidal anti-inflammatory drugs Nepafenac for treating ophthalmic disorders provide their action by inhibiting the activity of Cyclooxygenase, an enzyme required for prostaglandin synthesis.
The antibacterial drugs for treating ophthalmic disorders either kill or inhibit the spread of bacteria. The suitable antibacterial drugs of the present invention may be selected from but not limited to gentamicin, tobramycin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, norfloxacin, lomefloxacin, finafloxacin, trovafloxacin, fusidic acid, silver nitrate, enoxacin azithromycin, erythromycin, amikacin, streptomycin, netilmycin, kanamycin, bacitracin, polymyxin B, neomycin, paramomycin, vancomycin, doxycycline, tetracyclines, rifampin, trimethoprim, sulfacetamide, chloramphenicol, cycloserine, ceftriaxone, co-amoxiclav. Preferably antibacterial may be tobramycin.
The antiviral drugs for treating ophthalmic disorders inhibit viral replication. The suitable antiviral drugs of the present invention may be selected from but not limited to ganciclovir, aciclovir, famciclovir, valaciclovir, trifluorothymidine, idoxuridine, penciclovir, vidarabine, cytarabine, bromo vinyl deoxyuridine, interferons, foscarnet, zidovudine, sorivudine, adenosine arabinoside. Preferably antiviral may be ganciclovir.
The antifungal drugs for treating ophthalmic disorders either kill or inhibit the spread of fungi. The suitable antifungal drugs of the present invention may be selected from but not limited to natamycin, clotrimazole, amorolfine, amphotericin B, anidulafungin, butoconazole, butenafine, caspofungin, ciclopirox olamine, econazole, fluconazole, flucytosine, griseofulvin, haloprogin, itraconazole, ketoconazole, micafungin, miconazole, miconazole nitrate, naftifine, nikkomycin Z, topical nystatin, liposomal nystatin, oxiconazole, posaconazole, pimaricin, ravuconazole, sulconazole, terbinafine, terconazole, tioconazole, tolnaftate, undecylenate, and voriconazole. Preferably antifungal may be natamycin. The novel pharmaceutical combination according to present invention effectively treats ophthalmic disorders; wherein Alcaftadine which acts by blocking histamine at H1 receptor site; Nepafenac which acts by inhibiting the activity of cyclooxygenase; antibacterial/antifungal drugs which kill or inhibit the spread of bacteria/fungi, antiviral drugs which inhibits viral replication.
The concentrations in the novel pharmaceutical combination of Alcaftadine, Nepafenac and antibacterial and/or antiviral and/or antifungal drug has been optimized; so that it provides maximum therapeutic effect with reduction in side effects in the treatment of ophthalmic disorders.
The pharmaceutical composition according to present invention may contain any suitable amount of Alcaftadine, Nepafenac, antibacterial preferably Tobramycin and/or antiviral preferably Ganciclovir and/or antifungal preferably Natamycin drug by weight of the composition. The concentration of Alcaftadine may ranges from about 0.0025% to 15% by weight of composition; preferably may ranges from about 0.005% to 1%; more preferably may ranges from about 0.05% to about 0.5%. The concentration of Alcaftadine may be 0.1 %, 0.15%, 0.2%, 0.25%, 0.3%, 0.35% and 0.4%. The concentration of Nepafenac may range from about 0.05% to 2% by weight of composition; preferably may ranges from 0.05% to 1 %; more preferably may ranges from about 0.05% to 0.5%. The concentration of Nepafenac may be 0.075%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, and 0.5%. The concentration of Tobramycin may range from about 0.05% to 5% by weight of composition; preferably may ranges from about 0.01% to 1%; more preferably may ranges from about 0.1 % to about 0.5%. The concentration of Tobramycin may be 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45% and 0.5%. The concentration of Ganciclovir may range from about 0.005% to 5% by weight of composition; preferably may ranges from about 0.05% to 2.5%; more preferably may ranges from about 0.01% to about 1%. The concentration of Ganciclovir may be 0.01 %, 0.05%, 0.075%, 0.1 %, 0.15%, 0.2%, 0.25, 0.3%%, 0.4%, 0.5%, 0.75% and 1%. The concentration of Natamycin may ranges from about 0.05% to 20% by weight of composition; preferably may ranges from about 0.1 % to 15%; more preferably may ranges from about 1 % to about 10%. The concentration of Natamycin may be 0.1%, 1 %, 2%, 2.5%, 3%, 5%, 7%, 7.5%, 8%, 9% and 10%.
The novel pharmaceutical combination of Alcaftadine, Nepafenac and antibacterial and/or antiviral and/or antifungal drug for the treatment of ophthalmic disorder provides maximum therapeutic effect with no side effects or reduction in side effects like capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, sticky sensation, conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing, vitreous detachment, headache, hypertension, nausea/vomiting, sinusitis, eye irritation, burning, eye redness, eye discharge, eye swelling, erythema of eyelid, increased lacrimation, blurred vision, nasopharyngitis, hypersensitivity reactions including swelling of the face or allergic dermatitis and somnolence. In another aspect of the present invention is to provide novel pharmaceutical composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug in the treatment of ophthalmic disorders.
The novel pharmaceutical combination of alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug of the present invention may be in the form of ophthalmic composition.
The novel pharmaceutical ophthalmic composition comprising combination of Alcaftadine and Nepafenac along with antibacterial and/or antiviral and/or antifungal drug for the treatment of ophthalmic disorders may be in the form of eye drop, solution, suspension, microemulsions, ointments, lotions, gels, injections, nanoparticles, liposomes, niosomes, hydrogels and like.
The novel pharmaceutical ophthalmic composition comprising combination of Alcaftadine, Nepafenac along with antibacterial and/or antiviral and/or antifungal drug and pharmaceutically acceptable excipient. The novel pharmaceutical ophthalmic composition comprising combination of Alcaftadine, Nepafenac along with antibacterial and/or anti-viral and/or antifungal drug of the present invention may contain one or more excipient selected from the group consisting of solubilizers, buffering agents, tonicity agents, viscosity enhancers, preservatives, antioxidants, pH regulators, chelating agents, surfactants and vehicles.
The examples of solubilizers include but not limited to polyethylene glycol, propylene glycol, polyoxyethylene monostearate, polyoxyethylene hydrogenated castor oil, polysorbate 80, cyclodextrin or combination thereof. The amount of solubilizers present in the composition may ranges from about 0.1 to 40%; preferably about 1 to 20%; more preferably about 2 to 8%.
The examples of buffering agents include but not limited to carbonate buffers, borate buffers, phosphate buffers, acetate buffers, citrates, gluconates, lactates, propionates and tromethamine buffers or combination thereof. The amount of buffer adjusted to achieve desired performance properties for the aqueous ophthalmic solution.
The examples of tonicity agents include but not limited to, mannitol, sorbitol, glycerin, sodium chloride and other electrolytes or combination thereof. The amount of tonicity agents present in the composition may ranges from about 0.01 % (w/v) to about 7% by weight of composition.
The examples of viscosity enhancers include but not limited to carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, chondroitin sulfate or combination thereof. The viscosity enhancers present in an amount less than about 10% by weight of the composition.
The examples of preservatives include but not limited to benzalkonium chloride, benzethonium chloride, parahydroxybenzoic acid esters, cetyl pyridinium chloride, sodium dehydroacetate, phenylethyl alcohol, chlorobutanol, phenylmercuric acetate, phenylmercuric nitrate or combination thereof. The amount of preservative present in the composition may ranges from about 0.001-0.05% by weight of composition; preferably about 0.005 to 0.030%; more preferably about 0.01 to 0.025%.
The examples of antioxidants include but not limited to Sodium bisulfite, Sodium metabisulfite, Ethylenediaminetetraacetic acid, Thiourea or combination thereof. The amount of antioxidizing agents present in an amount less than about 5% by weight of the composition.
The examples of pH regulators include but not limited to citric acid, acetic acid, hydrochloric acid, phosphoric acid, sodium carbonate, sodium hydroxide, potassium hydroxide or combination thereof. The compositions of the present invention have a pH ranges from 4-9. Preferably, the pH of the compositions is 6.5-8.
The examples of chelating agents include but not limited to EDTA and its salts. The amount of chelating agents present in the composition may ranges from about 0.001-2% by weight of composition.
The examples of surfactants include but not limited to propylene glycol, tyloxapol, poloxamers, sorbitan esters, polyoxyl stearates, polysorbates, polyoxyethylene castor oil derivatives, caprylocaproyl polyoxyl-8 glycerides or combination thereof. The amount of surfactant present in the composition may ranges from about 0.1 to 40% by weight of composition; preferably about 1 % to 20%; more preferably 2 to 8%.
The examples of vehicle include but not limited to sterile purified water, propylene glycol, oils such as olive oil, castor oil, sesame oil or combination thereof.
In another aspect of the present invention is to provide process of preparing novel pharmaceutical composition comprising combination of Alcaftadine, Nepafenac along with antibacterial and/or antiviral and/or antifungal drug and pharmaceutically acceptable excipients in the treatment of ophthalmic disorders. The process of manufacturing ophthalmic composition according to present invention involves mixing Nepafenac and Alcaftadine with either antibacterial or antiviral or antifungal agent along with one or more pharmaceutically acceptable excipients like solubilizers, buffering agents, tonicity agents, viscosity enhancers, preservatives, antioxidants, pH regulators, chelating agents, surfactants and vehicles; and filtering the resulting solution through micron filter. The ophthalmic compositions according to present invention were evaluated for appearance, assay, pH, osmolarity, particulates foreign matter, sterility and found to be within the specifications.
The novel pharmaceutical ophthalmic composition of the present invention may be filled in to the single dose container or multiple dose containers and packaged into the plastic or glass containers.
EXAMPLES:
The following Examples are provided solely for illustrative purposes and are not meant to limit the invention in any way.
Example 1 :
Figure imgf000013_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
3. Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Caprylocaproyl polyoxyl-8 glycerides.
4. Solution of Step: 1 was added to mixture of Step: 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
5. Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.
Example 2:
Figure imgf000014_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
3. Benzalkonium chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Caprylocaproyl polyoxyl-8 glycerides.
4. Solution of Step: 1 was added to mixture of Step : 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
5. Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.
Example 3:
Figure imgf000015_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
3. Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Caprylocaproyl polyoxyl-8 glycerides.
4. Solution of Step :1 was added to mixture of Step : 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
5. Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.
Example 4:
Figure imgf000016_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
3. Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil.
4. Solution of Step: 1 was added to mixture of Step: 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
5. Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.
Example 5:
Figure imgf000017_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol. 2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
3. Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil.
4. Solution of Step: 1 was added to mixture of Step : 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
5. Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.
Example 6:
Figure imgf000018_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
3. Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil.
4. Solution of Step: 1 was added to mixture of Step: 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
5. Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.
Example 7:
Figure imgf000019_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
3. Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Polysorbate.
4. Solution of Step: 1 was added to mixture of Step: 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
5. Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.
Example 8:
Figure imgf000020_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
3. Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Polysorbate.
4. Solution of Step: 1 was added to mixture of Step: 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
5. Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.
Example 9:
Figure imgf000021_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
3. Benzalkonium chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Polysorbate.
4. Solution of Step: 1 was added to mixture of Step: 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
5. Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.
Example 10:
Figure imgf000022_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
3. Benzalkonium Chloride, Alcaftadine and Ganciclovir were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Polysorbate.
4. Solution of Step: 1 was added to mixture of Step : 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
5. Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.
Example 11 :
Figure imgf000023_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
Benzalkonium chloride, Alcaftadine and Natamycin were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Polysorbate. Solution of Step: 1 was added to mixture of Step: 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.
Example 12:
Figure imgf000024_0001
Manufacturing Process:
1. Nepafenac dissolved in a mixture of Polyethylene glycol and propylene glycol.
2. Buffer solution was prepared by dissolving Dibasic Sodium Phosphate, Monobasic Potassium Phosphate, in purified water under stirring, pH of the buffer was adjusted to pH 7.0 by using Sodium Hydroxide. Sodium Chloride as tonicity agent and Ethylene Diamine Tetra Acetic Acid as chelating agent were added to the buffer solution.
3. Benzalkonium Chloride, Alcaftadine and Tobramycin were dissolved in a separate vessel containing mixture of pH 7.0 buffer, Polyoxyl castor oil and Polysorbate.
4. Solution of Step: 1 was added to mixture of Step: 3 under continuous stirring till clear solution was obtained, final volume was made up using pH 7.0 buffer.
5. Batch was filtered using 0.2-micron filter and packed in 5.0 ml LDPE bottles.

Claims

1. A pharmaceutical composition comprising Alcaftadine and Nepafenac.
2. The pharmaceutical composition according to claim 1 , wherein the wherein the amount of Alcaftadine ranges from 0.05% to about 0.5% by weight of composition, preferably 0.25%.
3. The pharmaceutical composition according to claim 1 , wherein the amount of Nepafenac ranges from 0.05% to about 0.5% by weight of composition, preferably 0.1 % or 0.3%.
4. The pharmaceutical composition according to any of the preceding claims further comprising an antibacterial drug and/or antiviral drug and/or antifungal drug.
5. The pharmaceutical composition according to claim 1 , wherein the composition is ophthalmic.
6. The pharmaceutical composition according to claim 4, wherein antibacterial drug may be selected from gentamicin, tobramycin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, norfloxacin, lomefloxacin, finafloxacin, trovafloxacin, fusidic acid, silver nitrate, enoxacin azithromycin, erythromycin, amikacin, streptomycin, netilmycin, kanamycin, bacitracin, polymyxin B, neomycin, paramomycin, vancomycin, doxycycline, tetracyclines, rifampin, trimethoprim, sulfacetamide, chloramphenicol, cycloserine, ceftriaxone, co-amoxiclav.
7. The pharmaceutical composition according to claim 6, wherein the antibacterial drug is preferably Tobramycin.
8. The pharmaceutical composition according to claim 4, wherein antiviral drug may be selected from ganciclovir, acyclovir, famciclovir, valaciclovir, trifluorothymidine, idoxuridine, penciclovir, vidarabine, cytarabine, bromo vinyl deoxyuridine, interferons, foscarnet, zidovudine, sorivudine, adenosine arabinoside.
9. The pharmaceutical composition according to claim 8, wherein the antiviral drug is Preferably Ganciclovir.
10. The pharmaceutical composition according to claim 4, wherein antifungal drug may be selected from natamycin, clotrimazole, amorolfine, amphotericin B, anidulafungin, butoconazole, butenafine, caspofungin, ciclopirox olamine, econazole, fluconazole, flucytosine, griseofulvin, haloprogin, itraconazole, ketoconazole, micafungin, miconazole, miconazole nitrate, naftifine, nikkomycin Z, topical nystatin, liposomal nystatin, oxiconazole, posaconazole, pimaricin, ravuconazole, sulconazole, terbinafine, terconazole, tioconazole, tolnaftate, undecylenate, and voriconazole.
11. The pharmaceutical composition according to claim 10, wherein the antifungal drug is preferably natamycin.
12. The pharmaceutical composition according to claim 1 further comprises one or more excipient selected from the group consisting of solubilizers, buffering agents, tonicity agents, viscosity enhancers, preservatives, antioxidants, pH regulators, chelating agents, surfactants and vehicles.
PCT/IB2018/052647 2017-04-19 2018-04-17 Novel pharmaceutical composition comprising combination of alcaftadine and nepafenac along with antibacterial and/or antiviral an/or antifungal drug Ceased WO2018193367A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021245610A3 (en) * 2020-06-04 2022-01-06 Zenvision Pharma Llp Novel pharmaceutical composition comprising combination of olopatadine and nepafenac

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013158961A1 (en) * 2012-04-19 2013-10-24 Allergan, Inc. Combination of a non-steroidal anti-inflammatory drug with an anti-histaminic drug intended for ophthalmic use
WO2016196367A1 (en) * 2015-05-29 2016-12-08 Sydnexis, Inc. D2o stabilized pharmaceutical formulations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013158961A1 (en) * 2012-04-19 2013-10-24 Allergan, Inc. Combination of a non-steroidal anti-inflammatory drug with an anti-histaminic drug intended for ophthalmic use
WO2016196367A1 (en) * 2015-05-29 2016-12-08 Sydnexis, Inc. D2o stabilized pharmaceutical formulations

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021245610A3 (en) * 2020-06-04 2022-01-06 Zenvision Pharma Llp Novel pharmaceutical composition comprising combination of olopatadine and nepafenac

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