WO2014120293A1 - Formulations ophthalmiques - Google Patents

Formulations ophthalmiques Download PDF

Info

Publication number
WO2014120293A1
WO2014120293A1 PCT/US2013/065607 US2013065607W WO2014120293A1 WO 2014120293 A1 WO2014120293 A1 WO 2014120293A1 US 2013065607 W US2013065607 W US 2013065607W WO 2014120293 A1 WO2014120293 A1 WO 2014120293A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
bromfenac
nsaid
pharmaceutically acceptable
chelating agent
Prior art date
Application number
PCT/US2013/065607
Other languages
English (en)
Inventor
Mandar V Shah
Prafulla CHAUDHARI
Deepak Bahri
Original Assignee
Sentiss Pharma Pvt.Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sentiss Pharma Pvt.Ltd. filed Critical Sentiss Pharma Pvt.Ltd.
Publication of WO2014120293A1 publication Critical patent/WO2014120293A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • 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
    • 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 the field of stable, ophthalmic formulations and methods for the treatment of ocular inflammation and pain after cataract surgery. It describes a stable, ophthalmic composition comprising a non-steroidal anti- inflammatory drug (NSAID). Specifically, the present invention is related to a stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients for the treatment of ocular inflammation and pain after cataract surgery.
  • the present invention is preferably devoid of any kind of preservatives.
  • the present invention provides a method for treating ocular inflammation and pain after cataract surgery wherein the method comprises a once a day topical application to the eye of a patient in need thereof of a therapeutically effective amount of a preservative-free stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients.
  • Bromfenac is 2-amino-3-(4-bromobenzoyl)phenylacetic acid, (see Japanese patent no. 2683676 corresponding to US patent no. 4,910,225). Bromfenac has been practically used as its sodium salt in the form of eye drops in the field of ophthalmology.
  • Bromfenac (chemical name 2-amino-3-(4-bromobenzoyl)phenylacetic acid) is a nonsteroidal anti- inflammatory agent, is disclosed in JP-A-23052/1977 and its corresponding US patent No. 4.045,576.
  • Bromfenac is effective against inflammatory diseases (e.g. blepharitis, conjunctivitis, scleritis, postoperative inflammation) of the extraocular segment or the anterior ocular segment in the field of ophthalmology, and in particular, its efficacy for treating uveitis is equal to nonsteroidal anti- inflammatory agents which have previously been used in the field of ophthalmology, and its sodium salt has been practically used in the form of eye drops.
  • inflammatory diseases e.g. blepharitis, conjunctivitis, scleritis, postoperative inflammation
  • nonsteroidal anti- inflammatory agents which have previously been used in the field of ophthalmology, and its sodium salt has been practically
  • the eye drop as mentioned above is designed to stabilize 2-amino-3-(4-bromobenzoyl)phenylacetic acid by means of addition of a water-soluble polymer (e.g. polyvinylpyrrolidone, polyvinyl alcohol, etc.) and a sulfite (e.g. sodium sulfite, potassium sulfite, etc.) (Japanese patent No. 2,683,676 and its corresponding US patent No. 4,910,225).
  • Japanese patent No. 2,954,356 corresponding to US patents Nos.
  • 5,603,929 and 5,653,972 discloses a stable ophthalmic composition which comprises incorporating an antibacterial quaternary ammonium polymer and boric acid into an acidic ophthalmic agent.
  • the acidic agent described therein includes, for example, 2-amino-3-(4-bromobenzoyl)phenylacetic acid.
  • BAC benzalkonium chloride
  • chlorhexidine chlorhexidine
  • thimerosal have excellent antimicrobial activity; however, it is now known that these small organic antimicrobials are often toxic to the sensitive tissues of the eye and can accumulate in cornea, contact lenses, particularly soft, hydrophilic contact lenses.
  • BAC a preservative
  • Medications with BAC may cause disruption of the corneal surface with lower concentrations of BAC.
  • BAC a preservative
  • Medications with higher concentration of BAC have been shown to cause much more disruption of the corneal surface compared to medications with lower concentrations of BAC.
  • NSAID non-steroidal anti-inflammatory drug
  • the present invention is preferably devoid of BAC, more preferably devoid of any kind of antimicrobial preservatives.
  • Bromfenac has some stability issues during their formulation preparation so, with expenditure of intellectual effort and careful experimentation the inventors of the present invention have prepared a preservative-free stable, ophthalmic composition by adding a step of continuous nitrogen purging during mixing & packaging of the ophthalmic composition.
  • NSAID non-steroidal antiinflammatory drug
  • method comprises a once a day topical application to the eye of a patient in need thereof of a therapeutically effective amount of a preservative-free stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients.
  • BAC benzalkonium chloride
  • BAC-free, preferably preservative-free, stable, ophthalmic composition wherein the said stable, ophthalmic composition has reduced the stability issues of bromfenac by adding a step of continuous nitrogen purging during mixing and packaging of the ophthalmic composition.
  • the present invention relates to a stable, ophthalmic composition
  • a stable, ophthalmic composition comprising a nonsteroidal anti-inflammatory drug (NSAID) and/or pharmaceutically acceptable excipients for the treatment of ocular inflammation and pain after cataract surgery.
  • NSAID nonsteroidal anti-inflammatory drug
  • the present invention relates to a preservative- free stable, ophthalmic composition
  • a preservative- free stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients for the treatment of ocular inflammation and pain after cataract surgery wherein the said stable, ophthalmic composition is devoid of any kind of preservatives.
  • Another aspect of the invention is a method for treating ocular inflammation and pain after cataract surgery wherein method comprises a once a day topical application to the eye of a patient in need thereof of a therapeutically effective amount of a preservative-free stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients.
  • the present invention provides a topical ophthalmic composition
  • a topical ophthalmic composition comprising a pharmaceutically acceptable non-steroidal anti- inflammatory drug (NSAID) in an aqueous carrier, wherein the composition is substantially free of preservatives.
  • NSAID non-steroidal anti- inflammatory drug
  • the present invention also provides a topical aqueous ophthalmic composition
  • a topical aqueous ophthalmic composition comprising bromfenac or a pharmaceutically acceptable salt thereof; boric acid; sodium borate; disodium edetate, EDTA, or a combination thereof; polysorbate 80; and sodium sulfite, sodium metabisulfite, or combination thereof; wherein the composition has a pH of 7-9, and the composition is substantially free of preservatives.
  • the present invention also provides a composition
  • a composition comprising: 0.6-0.9 mg/ml bromfenac or a pharmaceutically acceptable salt thereof, based on the amount of bromfenac free base; 11-15 mg/ml boric acid; 11-15 mg/ml sodium borate; 0.25-2 millimolar disodium edetate, EDTA, or combination thereof; 1.5-3.5 mg/ml polysorbate 80; and 2-3.5 mg/ml sodium sulfite, sodium metabisulfite, or combination thereof.
  • the present invention also includes methods of using the inventive compositions.
  • the present invention preferably provides a method of treating ocular inflammation or pain in a subject in need of such treatment, the method preferably comprising administering to a subject in need thereof a topical ophthalmic composition preferably comprising a pharmaceutically effective amount of a pharmaceutically acceptable non-steroidal antiinflammatory drug (NSAID) in an aqueous carrier, wherein the composition is preferably substantially free of preservatives.
  • NSAID non-steroidal antiinflammatory drug
  • the present invention also provides processes for manufacturing the inventive compositions.
  • the present invention preferably provides a process comprising combining a non-steroidal anti- inflammatory drug (NSAID) with an aqueous composition in a preferably substantially oxygen- free atmosphere to form a pharmaceutical composition.
  • NSAID non-steroidal anti- inflammatory drug
  • the present invention also provides a process of preparing a preservative-free, stable, ophthalmic composition, the process preferably comprising a) combining a first portion of water with a first component of a buffer system to form a first composition; b) combining the first composition a second component of a buffer system to form a second composition; c) combining the second composition with a chelating agent to form a third composition; d) combining the third composition with an antioxidant to form a fourth composition; e) combining the fourth composition with a surfactant to form a fifth composition; f) combining the fifth composition with an NSAID to form a sixth composition; g) verifying that the pH of the sixth composition is 7-8.5; and h) adding a second portion of water to obtain the ophthalmic composition.
  • the person of ordinary skill in the art will appreciate that there is some flexibility with respect to the order of these actions.
  • composition of the present invention is preferably packaged in a single-use container.
  • the present invention also preferably provides a kit comprising the inventive composition contained in a single-use container.
  • the single-use container preferably comprises LDPE, HDPE or polypropylene.
  • the single-use container is preferably sterile.
  • the present invention also provides a process of stabilizing a preservative-free ophthalmic composition, wherein a chelating agent in the ophthalmic composition preferably decreases production of total impurities in the composition compared to a comparative formulation having the same ingredients, but having less or no chelating agent.
  • the NSAID preferably comprises bromfenac or a pharmaceutically acceptable salt thereof.
  • composition of the present invention is preferably substantially free of preservatives.
  • any ophthalmically suitable chelating agent, or combination of chelating agents may be used.
  • the chelating agent preferably comprises disodium edetate, EDTA, or a combination thereof.
  • the composition of the present invention preferably comprises chelating agent in the amount of 0.25-6 millimolar, or about 0.1-2 mg/ml. Any suitable amount may be used and can be determined by one of skill in the art.
  • chelating agent may be preferably present in an amount of at least, or about, 0.1 or 0.2 mg/ml, and/or in an amount up to, or about, 2 or 1 mg/ml.
  • the composition is preferably stable at 50 Deg. C for one month.
  • the composition preferably has a pH from about 7 to about 9, more preferably a pH from about 7.8 to about 8.8.
  • compositions of the present invention preferably comprise an antioxidant.
  • the antioxidant preferably comprises sodium sulfite, sodium metabisulfite, or a combination thereof.
  • Compositions of the present invention preferably comprise a surfactant.
  • the surfactant preferably comprises polysorbate 80.
  • Methods of the present invention preferably comprise once a day application to the eye of the patient.
  • Processes of the present invention preferably include combining water with a buffer system, a chelating agent, an antioxidant, a surfactant, and an NSAID.
  • the combining is preferably done in a nitrogen atmosphere.
  • Processes preferably comprise determining the pH of the composition.
  • Processes preferably comprise adjusting the pH to 7-9.
  • the first buffer component preferably comprises boric acid and the second buffer component preferably comprises sodium borate, or the first buffer component preferably comprises sodium borate and the second buffer component preferably comprises boric acid.
  • the first portion of water preferably comprises about 80% of batch volume, and the second portion of water preferably comprises about 20% of batch volume.
  • the verifying preferably comprises determining pH of the sixth composition. In processes of the present invention, the verifying preferably comprises adjusting the pH to 7-8.5. Processes of the present invention preferably comprise filling the ophthalmic composition in a sterile container, preferably a single-use container.
  • the present invention provides a topical stable, ophthalmic composition
  • a topical stable, ophthalmic composition comprising a pharmaceutically acceptable non-steroidal anti- inflammatory drug (NSAID) in an aqueous carrier, wherein the composition is substantially free of BAC, more preferably substantially free of preservatives.
  • NSAID non-steroidal anti- inflammatory drug
  • the invention also provides a method of treating ocular inflammation or pain in a subject in need of such treatment, the method comprising administering to a subject in need thereof a topical stable, ophthalmic composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable non-steroidal anti- inflammatory drug (NSAID) in an aqueous carrier, wherein the composition is substantially free of BAC, more preferably substantially free of preservatives.
  • NSAID non-steroidal anti- inflammatory drug
  • the invention also provides a method comprising combining a non-steroidal antiinflammatory drug (NSAID) with an aqueous composition in a substantially oxygen-free atmosphere to form a pharmaceutical composition.
  • NSAID non-steroidal antiinflammatory drug
  • the NSAID preferably comprises bromfenac or a pharmaceutically acceptable salt thereof.
  • the composition preferably comprises at least one of a buffer system, an antioxidant, and a chelating agent.
  • the composition is preferably packaged in a single-use container.
  • bromfenac is preferably present in a concentration of 0.5-1 mg/ml (based on bromfenac free base).
  • the NSAID preferably bromfenac or a therapeutically acceptable salt thereof, may be present in any amount that is therapeutically effective.
  • the amount is preferably at least 0.1, 0.2, 0.3 0.4, 0.5 or 0.6 mg/ml of the composition, based on weight of NSAID free base.
  • the amount is preferably up to 1.5, 1.4, 1.3, 1.2, or 1.1 mg/ml.
  • Some more preferred amounts include 0.5, 0.6, 0.7, 0.8, and 0.9 mg/ml and ranged formed from these values.
  • the present invention provides a stable, ophthalmic composition
  • a non-steroidal anti-inflammatory drug (NSAID) and/or pharmaceutically acceptable excipients for the treatment of ocular inflammation and pain after cataract surgery.
  • NSAID non-steroidal anti-inflammatory drug
  • the present invention provides a BAC-free, preferably preservative-free, stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients for the treatment of ocular inflammation and pain after cataract surgery.
  • the present invention provides a BAC-free, preferably preservative-free, stable, ophthalmic composition wherein the stable, ophthalmic composition is devoid of any kind of preservatives for better patient compliance.
  • One of the preferred embodiments of the present invention provides a preservative-free stable, ophthalmic composition wherein the said stable, ophthalmic composition has reduced the stability issues of bromfenac by adding a step of continuous nitrogen purging during mixing & packaging of the ophthalmic composition.
  • compositions of the present invention comprise one or more chelating agent.
  • the chelating agent is preferably provided in sufficient concentration to decrease metal ion catalysed degradation, preferably resulting in reduction of total impurities. Any suitable amount of chelating agent may be used. Preferably, at least 0.25, 0.5 or 1 millimolar (micromoles/milliliter) chelating agent is used. Preferably up to 6, 3, or 2 millimolar chelating agent is used. Some preferred amounts include 0.54 and 2.7 millimolar.
  • chelating agents include disodium edetate and ethylenediamine tetraacetic acid ("EDTA").
  • excipients used are ophthalmic ally acceptable which includes, without limitation, buffering agents, chelating agents, tonicity agents, stabilising agents, permeation enhancers, antioxidants, pH adjusting agents and surfactants.
  • preservative- free ophthalmic compositions can be prepared as one of the embodiments of the present invention to make the composition pharmaceutically acceptable for used as a single unit dose to avoid or reduce ocular toxicity experiencing hypersensitivity reactions to the patients provided by the known preservatives used to preserve the ophthalmic preparation in the prior of this invention.
  • buffering agents used in the present invention includes but are not limited to acetate buffers, citrate buffers, phosphate buffers and borate buffers, sodium dihydrogen phosphate dihydrate, dibasic sodium phosphate heptahydrate, monobasic sodium phosphate, boric acid, borax, citric acid, citric acid monohydrate or ⁇ -aminocaproic acid, with citrate and borate buffers being preferred. Any amount of buffering agents may be used and can be determined by one of skill in the art using the present disclosure for guidance.
  • the acid part of the buffer can comprise at least about 1 or 2 mg/ml and/or up to about 15 or 8 mg/ml.
  • the salt part of the buffer can comprise at least about 5, 1.5, or 3 mg/ml and/or up to about 15, 10, or 6 mg/ml.
  • borate buffer preferred amounts are generally about 3-15 mg/ml sodium borate and about 2-15 mg/ml boric acid.
  • citrate buffer preferred amounts are generally about 0.5-6 mg/ml sodium citrate and about 1-8 mg/ml citric acid.
  • the present invention may include chelating agents such as disodium edetate or ethylenediamine tetraacetic acid (“EDTA”), diammonium EDTA, dipotassium EDTA, calcium disodium EDTA, hydroxyethylethylenediaminetriacetic acid (“HEDTA”), ethylenediaminetetraacetic acid, mono(triethanolamine) salt (“TEA-EDTA”), tetrasodium EDTA, tripotassium EDTA, trisodium phosphate, diammonium citrate, galactaric acid, galacturonic acid, gluconic acid, glucuronic acid, humic acid, cyclodextrin, potassium citrate, the potassium salt of ethylenediamine-tetra (methylene phosphonic acid) (“EDTMP”), sodium citrate, sodium EDTMP, and the like.
  • EDTA ethylenediamine tetraacetic acid
  • HEDTA hydroxyethylethylened
  • acids or bases can also be used to adjust the pH of ophthalmic compositions as required.
  • the pH range of the ophthalmic compositions should preferably be maintained from about 7.0 to about 9.0 or greater, preferably about 7.0 to about 8.5, with an appropriate buffer system and pH adjusting agents so that the ophthalmic compositions are ophthalmically acceptable.
  • tonicity adjusting agents may be added and include, without limitation, glycerin, sorbitol, sodium chloride, potassium chloride, and mannitol, dextrose, propylene glycol and combinations thereof or any other suitable ophthalmically acceptable tonicity adjusting agents. All combinations of two or more tonicity agents are expressly contemplated, with a combination of mannitol and sodium chloride being especially preferred. Any amount of tonicity agent may be used and can be determined by one of skill in the art using this disclosure as guidance. The tonicity agent, when used, will generally be present in an amount up to, or about, 40, 35, 25, or 15 mg/ml. Some preferred amounts include 31, 28.5, 9, and 6.5 mg/ml.
  • vehicles can also be used in the ophthalmic compositions of the present embodiments.
  • These vehicles include, but are not limited to, polyvinyl alcohol, povidone, methyl cellulose, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, poly ethylene glycol, hyaluronic acid, polygalacturonic acid, xyloglucan, carbopol, polycarbophil, gellan gum physiological saline solution, water, purified water, and combinations thereof.
  • antioxidants can be included in the present invention compositions.
  • Suitable antioxidants include, but are not limited to, sodium sulphite, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene and the like and mixtures thereof.
  • Sodium sulphite and sodium metabisulphite are especially preferred.
  • antioxidant is preferably present in an amount less than or about 5, 4, 3, 2, or 1 mg/ml. While there is no particular preferred lower limit, when used, antioxidant will generally comprise at least or about 0, 1 or 5 mg/ml.
  • the surfactants that may be used is selected from the group consisted of, but are not limited to sodium lauryl sulfate, docusate sodium, polyoxyalkyl ethers, polyoxylalkyl phenyl ethers, polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxyl 40 stearates, polyoxy hydrogenated castor oil, polyoxy sorbitan esters, sorbitan esters, polysorbates, polyoxyl 35 castor oil, sorbitan mono laureates, poloxamer and mixtures thereof.
  • any ophthalmically suitable surfactant, or combination of surfactants may be used.
  • Polysorbate 80 is preferred. Any suitable amount may be used and can be determined by one of skill in the art.
  • surfactant may be preferably present in an amount of at least, or about, 0.5 or 1 mg/ml, and/or in an amount up to, or about, 2 or 3 mg/ml.
  • the excipients used in the present invention are preferably pharmaceutically and ophthalmically acceptable in nature.
  • the excipients used in the present invention are preferably selected to be non-toxic and have no substantial detrimental effect (preferably, in the amount used) on the present ophthalmic compositions, on the use of the compositions or on the human or animal to which the ophthalmic compositions are to be administered.
  • the present invention provide the ophthalmic compositions in the form of aqueous liquids, solutions, microemulsions, nanoemulsion, nano reservoir system, in-situ gel drops, nanop articulate system, liposomal drops, bioadhesive gel drops, drops, etc.
  • the present invention preferably provides the ophthalmic compositions for topical ophthalmic delivery comprising administering said composition in the eyes, ear, and/or nose of the humans or animals.
  • the present invention preferably provides the ophthalmic compositions for topical ophthalmic delivery for once-a-day administration.
  • the present invention provides methods of treating ocular inflammation and pain after cataract surgery by administering a stable, ophthalmic composition comprising a non-steroidal anti-inflammatory drug (NSAID) and/or pharmaceutically acceptable excipients.
  • NSAID non-steroidal anti-inflammatory drug
  • the present invention provides methods of treating ocular inflammation and pain after cataract surgery by administering a stable, ophthalmic composition comprising a BAC-free (preferably preservative-free) stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients.
  • a stable, ophthalmic composition comprising a BAC-free (preferably preservative-free) stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients.
  • the stable, ophthalmic composition of the present composition has an ophthalmically acceptable osmolality or tonicity level.
  • a preferred osmolality is at least about 250 mOsmol/kg and/or less than or equal to about 350 mOsmol/kg.
  • the osmolality or tonicity of the carrier component substantially corresponds to the tonicity of the fluids of the eye, in particular the human eye.
  • the present invention provides a process of preparing a stable, ophthalmic composition wherein the composition comprises a non-steroidal antiinflammatory drug (NSAID) and/or pharmaceutically acceptable excipients.
  • NSAID non-steroidal antiinflammatory drug
  • the present invention provides a process of preparing a stable, ophthalmic composition wherein the composition comprises a preservative- free stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients.
  • the present invention provides a process of preparing a preservative- free stable, ophthalmic composition wherein the composition is prepared by a process comprising, preferably with continuous nitrogen sparging, :
  • step 3 Add another component of a buffer system (e.g. sodium borate) to step 1 or 2 under stirring and mix until dissolved.
  • a buffer system e.g. sodium borate
  • step 4 Add chelating agent (e.g., disodium edetate) to step 3 under stirring and mix until dissolved.
  • chelating agent e.g., disodium edetate
  • step 4 Add anti-oxidant (e.g., sodium sulphite) to step 4 under stirring and mix until dissolved.
  • anti-oxidant e.g., sodium sulphite
  • surfactant e.g., polysorbate 80
  • NSAID e.g., bromfenac
  • the present invention provides a method of using a preservative- free stable, ophthalmic composition of the present invention for the management of ocular inflammation and pain after cataract surgery, which comprises administering to a subject in need thereof the preservative- free stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients.
  • the present invention provides use of a preservative-free stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients in the preparation of a medicament for the management of ocular inflammation and pain after cataract surgery.
  • the invention includes a kit comprising a preservative- free stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients, the composition being contained within a container prepared from a pharmaceutically acceptable packaging material.
  • a pharmaceutically acceptable packaging material may be use, preferably packaging material that is suitable for containing ophthalmic compositions, more preferably bromfenac ophthalmic compositions.
  • Packaging materials include but are not limited to low density polyethylene (“LDPE”), high density polyethylene (“HDPE”), polypropylene, polystyrene, polycarbonate, polyesters (such as polyethylene terephthalate and polyethylene naphthalate), nylon, polyvinyl chloride), poly(vinylidine chloride), poly(tetrafluoroethylene) and other materials known to those of ordinary skill in the art.
  • Flexible bottles prepared from, or comprising, LDPE, HDPE or polypropylene are particularly preferred.
  • Preferred containers include bottles, preferably a dropper (e.g., a bottle or ampule suitable for dropwise application of the composition), more preferably, a single-use bottle or dropper.
  • the containers are preferably sterilized, preferably prior to filling. Any suitable method can be used to sterilize the containers, and can be determined by the person of ordinary skill in the art. Some preferred methods include exposure to gamma irradiation and/or exposure to ethylene oxide gas.
  • compositions are preferably sterile.
  • An article comprising the composition filled in a container is preferably sterile, preferably at the time the container is filled.
  • the compositions are preferably filled into sterile containers, preferably single-use containers.
  • Formulations of Bromfenac preservative- free are prepared with ranges of ingredients as shown in Table 1, and exposed to stress studies at 50 Deg. C for 0 day; 15 days and 30 days to determine the stability of the proposed formulations. Some specific formulations are shown in Table 2.
  • a non- accelerated study method may be used to test stability.
  • a preferred stress study comprises placing the composition/solution is filled in Opaque LDPE vial with LDPE nozzle and HDPE cap, packing in secondary packaging material, and maintaining at 50 Deg. C in the dark. Impurities are measured by HPLC for initial (0 days), 15 days & 30 days.
  • the impurities preferably measured include Impurity A (7-(4-Bromobenzoyl)-l,3-dihydro-2H-indol- 2-one), and total impurities, as well as identification of the amount of the highest unknown impurity.
  • the formulations are evaluated for bromfenac content and related substances at fifteen
  • the formulations are evaluated for bromfenac content and related substances at thirty (30) days:
  • Formulas I, II, and III exhibit good stability following the stress stability test at 50 Deg. C for 1 month (e.g., 30 days).
  • step 2 Add boric acid to step 1 under stirring and mix until dissolved.
  • step 3 Add sodium borate to step 2 under stirring and mix until dissolved.
  • step 4 Add disodium edetate to step 3 under stirring and mix until dissolved.
  • step 5 Add Sodium sulfite anhydrous to step 4 under stirring and mix until dissolved.
  • step 2 Add boric acid to step 1 under stirring and mix until dissolved.
  • step 3 Add sodium borate to step 2 under stirring and mix until dissolved.
  • step 4 Add disodium edetate to step 3 under stirring and mix until dissolved.
  • step 5 Add Sodium sulfite anhydrous to step 4 under stirring and mix until dissolved.
  • step 2 Add boric acid to step 1 under stirring and mix until dissolved.
  • step 3 Add sodium borate to step 2 under stirring and mix until dissolved.
  • step 4 Add disodium edetate to step 3 under stirring and mix until dissolved.
  • step 5 Add Sodium metabisulfite to step 4 under stirring and mix until dissolved.
  • the Bromfenac content is measured and found to be 97.3% (Limit: 90.0 -110.0%), the Highest unknown impurity is measured and found to be 0.02% (Limit: NMT 1.0%) and total impurity is measured and found to be 0.68% (Limit: NMT 3.0%).
  • the Bromfenac content is measured to be 96.2% (Limit: 90.0 -110.0%), the Highest unknown impurity is measured to be 0.46% (Limit: NMT 1.0%) and total impurity is measured to be 1.51% (Limit: NMT 3.0%).
  • the Bromfenac content is measured to be 96.2% (Limit: 90.0 -110.0%), the Highest unknown impurity is measured to be 0.42% (Limit: NMT 1.0%) and total impurity is measured to be 1.41% (Limit: NMT 3.0%).
  • Polysorbate 80 concentrations at or above 3.5mg/ml may be unstable during stress stability at 50 Deg. C for 1 month.
  • Bromfenac content is measured to be 90.4% (Limit: 90.0 -110.0%), the highest unknown impurity is measured to be 0.65% (Limit: NMT 1.0%) and total impurity is measured to be 2.43% (Limit: NMT 3.0%).
  • step 2 Add boric acid to step 1 under stirring and mix until dissolved.
  • step 3 Add sodium borate to step 2 under stirring and mix until dissolved.
  • step 4 Add disodium edetate to step 3 under stirring and mix until dissolved.
  • step 5 Add sodium Sulphite to step 4 under stirring and mix until dissolved.
  • step 2 Add sodium borate to step 2 under stirring and mix until dissolved.
  • step 2 Add Citric acid to step 1 under stirring and mix until dissolved.
  • step 3 Add Sodium Citrate to step 2 under stirring and mix until dissolved.
  • step 4 Add Sodium chloride to step 3 under stirring and mix until dissolved.
  • step 5 Add Mannitol to step 4 under stirring and mix until dissolved.
  • step 6 Add disodium edetate dihydrate to step 5 under stirring and mix until dissolved.
  • the preservative-free stable, ophthalmic composition of the present invention can be used for the management of ocular inflammation and pain after cataract surgery, which comprises administering to a subject in need thereof the stable, ophthalmic composition comprising bromfenac and/or pharmaceutically acceptable excipients.
  • bromfenac compositions may also be used for other bromfenac concentrations without any need to adjust the carrier vehicle or method of manufacture, though adjustments may be made if desired.

Landscapes

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

Abstract

L'invention concerne une composition ophtalmique stable comprenant un médicament anti-inflammatoire non stéroïde (NSAID) et/ou des excipients pharmaceutiquement acceptables ainsi que leurs procédés de production et d'utilisation. Les compositions sont de préférence exemptes de BAC et idéalement exemptes de conservateurs.
PCT/US2013/065607 2013-01-31 2013-10-18 Formulations ophthalmiques WO2014120293A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201361759089P 2013-01-31 2013-01-31
US61/759,089 2013-01-31
US201361783717P 2013-03-14 2013-03-14
US61/783,717 2013-03-14

Publications (1)

Publication Number Publication Date
WO2014120293A1 true WO2014120293A1 (fr) 2014-08-07

Family

ID=51262823

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/065607 WO2014120293A1 (fr) 2013-01-31 2013-10-18 Formulations ophthalmiques

Country Status (1)

Country Link
WO (1) WO2014120293A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262346A (zh) * 2014-09-17 2015-01-07 广东众生药业股份有限公司 一种溴芬酸钠二聚体杂质的制备方法
US20170190634A1 (en) * 2015-02-25 2017-07-06 Nichem Solutions Plant growth promoting composition and a process of preparing the same
CN114224830A (zh) * 2021-12-24 2022-03-25 辰欣药业股份有限公司 一种单剂量无抑菌剂的眼用制剂及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070287749A1 (en) * 2003-01-21 2007-12-13 Ista Pharmaceuticals, Inc. Bromfenac ophthalmic formulations and methods of use
US20100130550A1 (en) * 2008-11-21 2010-05-27 Bridge Pharma, Inc. Ocular formulations of norketotifen
WO2011127196A1 (fr) * 2010-04-09 2011-10-13 Allergan, Inc. Compositions de kétorolac pour la cicatrisation de lésions cornéennes
WO2012127497A1 (fr) * 2011-03-04 2012-09-27 Cadila Healthcare Limited Compositions pharmaceutiques stables de kétorolac ou des sels de celui-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070287749A1 (en) * 2003-01-21 2007-12-13 Ista Pharmaceuticals, Inc. Bromfenac ophthalmic formulations and methods of use
US20100130550A1 (en) * 2008-11-21 2010-05-27 Bridge Pharma, Inc. Ocular formulations of norketotifen
WO2011127196A1 (fr) * 2010-04-09 2011-10-13 Allergan, Inc. Compositions de kétorolac pour la cicatrisation de lésions cornéennes
WO2012127497A1 (fr) * 2011-03-04 2012-09-27 Cadila Healthcare Limited Compositions pharmaceutiques stables de kétorolac ou des sels de celui-ci

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AYAKI, M ET AL.: "Cytotoxicity of ophthalmic solutions with and without preservatives to human corneal endothelial cells, epithelial cells and conjunctival epithelial cells.", CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY., vol. 36, 2008, pages 553 - 559 *
EPSTEIN, SP ET AL.: "Comparative toxicity of preservatives on immortalized corneal and conjunctival epithelial cells.", JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS., vol. 25, no. 2, 2009, pages 113 - 119 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262346A (zh) * 2014-09-17 2015-01-07 广东众生药业股份有限公司 一种溴芬酸钠二聚体杂质的制备方法
US20170190634A1 (en) * 2015-02-25 2017-07-06 Nichem Solutions Plant growth promoting composition and a process of preparing the same
US10407352B2 (en) * 2015-02-25 2019-09-10 Nichem Solutions Plant growth promoting composition and a process of preparing the same
CN114224830A (zh) * 2021-12-24 2022-03-25 辰欣药业股份有限公司 一种单剂量无抑菌剂的眼用制剂及其制备方法

Similar Documents

Publication Publication Date Title
US20220175726A1 (en) Stable preservative-free mydriatic and anti-inflammatory solutions for injection
KR101560429B1 (ko) 눈의 통증을 치료 또는 예방하기 위한 케토롤락 트로메타민 조성물
RU2740910C2 (ru) Офтальмологическая композиция, содержащая повидон-иод
US12070442B2 (en) Ophthalmic pharmaceutical compositions and methods for treating ocular surface disease
US9801813B2 (en) Preservative-free ophthalmic pharmaceutical formulation
WO2014204952A1 (fr) Solution de bromfénac stable
WO2014120293A1 (fr) Formulations ophthalmiques
EP2919755B1 (fr) Composition aqueuse liquide contenant de l'acide 2-amino-3-(4-bromobenzoyl)-phénylacétique
US20170000889A1 (en) Stable bromfenac ophthalmic solution
US20230277557A1 (en) Pharmaceutical kits and their use for treating dry eye disease
EP2730292A1 (fr) Composition ophtalmique aqueuse
EP3593788A1 (fr) Compositions ophtalmiques contenant un prostamide libérant de l'oxyde nitrique
WO2019107569A1 (fr) Produit ophtalmique
JP5794977B2 (ja) アニオン性治療剤を含む水性眼用組成物
WO2022076398A1 (fr) Kits pharmaceutiques et leur utilisation pour traiter le syndrome de l'oeil sec

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13874012

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13874012

Country of ref document: EP

Kind code of ref document: A1