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EP2389069A1 - Procédés et compositions pour le traitement et la prévention d'infections - Google Patents

Procédés et compositions pour le traitement et la prévention d'infections

Info

Publication number
EP2389069A1
EP2389069A1 EP10733709A EP10733709A EP2389069A1 EP 2389069 A1 EP2389069 A1 EP 2389069A1 EP 10733709 A EP10733709 A EP 10733709A EP 10733709 A EP10733709 A EP 10733709A EP 2389069 A1 EP2389069 A1 EP 2389069A1
Authority
EP
European Patent Office
Prior art keywords
suitable composition
ophthalmologically suitable
composition
ophthalmologically
eye
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10733709A
Other languages
German (de)
English (en)
Inventor
Jeffrey P. Gilbard
Robert B. Huson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Advanced Vision Research LLC
Original Assignee
Advanced Vision Research LLC
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 Advanced Vision Research LLC filed Critical Advanced Vision Research LLC
Publication of EP2389069A1 publication Critical patent/EP2389069A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/20—Elemental chlorine; Inorganic compounds releasing chlorine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/40—Peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • a condition known as dry eye causes chronic eye irritation resulting from decreased tear production or increased evaporation that results in a loss of water from the tear film and an increase in tear film osmolarity. This increase in tear film osmolarity results in an osmotic dehydration of the surface associated with a decrease in the density of conjunctival goblet cells.
  • dry eye patients have increased bacterial colonization of their eyelids, and that the bacteria found in these patients decrease the proliferation of conjunctival goblet cells in tissue culture (Graham et al Analysis of Bacterial Flora in Dry Eye, Ocular Surface, 3(1):S68, 2005).
  • Dry-eye patients are also known to be more prone to eye infections, especially in the context of contact lens wear (Lemp MA "Is the dry eye contact lens wearer at risk?", Cornea (United States), 1990, 9 Suppl 1 pS48-50; discussion S54).
  • Punctal plugs are a frequently used treatment for dry eye. They provide symptomatic relief for patients with dry eye, reduce elevated tear film osmolarity in the disease and reduce ocular surface staining.
  • a problem with punctal plugs is that they are frequently colonized by pathogenic noncomensals, including Pseudomonas aeruginosa and Staphylococcus aureus, that may cause symptoms and increase the risk of eye infections (Soukiasian SH Microbiology of Explanted Punctal Plugs, ARVO Annual Meeting, Program#/Poster# 4981/B305, April 29, 2004; Sugita J, Yokoi N, Fullwood NJ, et al.
  • Bacterial overgrowth has been hypothesized to contribute to the symptoms of blepharitis by the production of bacterial lipases and esterases that hydrolyze the wax and sterol esters in meibum, creating free fatty acids that are irritating to ocular tissue and may effect tear film stability (Ta CN, Shine WE, McCulley JP, et al., Cornea (United States), Aug 2003, 22(6) p545-8).
  • these fatty acids may promote eyelid and ocular surface inflammation (Shine WE, McCulley JP, Pandya AG Exp Eye Res (England), Apr 2003, 76(4) p417-20).
  • Chlorine dioxide has been called the ideal biocide. Despite the many advantages of chlorine dioxide, commercial use is limited because it is an unstable, highly reactive gas which is soluble in and decomposes in water. See, e.g., U.S. Pat. No. 4,941,917. Therefore, it has heretofore been necessary to generate aqueous chlorine dioxide solutions on site for immediate use or use within a relatively short time (typically less than an hour). Due to these limitations, chlorine dioxide has not met its full potential as an antimicrobial agent. Similarly, other oxidizing antimicrobial agents such as sodium perborate have been under utilized because of stability and effectiveness issues. Therefore, a need exists for improved preparations that can be used, for example, in or around the eye and that are stable for extended periods of time.
  • the instant invention is based on the discovery that eye care preparations comprising an activated oxidizing antimicrobial agent such as chlorine dioxide exhibit beneficial antimicrobial effects.
  • preparations comprising activated chlorine dioxide are useful for the treatment and prevention of microbial infection and for the preservation of ocular products.
  • the addition of chlorine dioxide preserves the solution for extended periods of time.
  • these preparations resist microbial growth prior to and after being used by an individual.
  • the instant invention provides ophthalmologically suitable compositions comprising activated chlorine dioxide, wherein the osmolality of the composition is less than 200 mOsmol/Kg.
  • a specific ophthalmologically suitable composition of the invention comprises activated chlorine dioxide, wherein the osmolality of the composition is less than 180 mOsm/Kg.
  • the cholorine dioxide can be present in a concentration of about 10-125 ppm, of about 25-75 ppm or about 50 ppm.
  • the ophthalmologically suitable composition can further comprise a weak acid, such as boric acid.
  • the ophthalmologically suitable composition can further comprise a buffer component, e.g., an inorganic buffer component such as borate, phosphate, or carbonate, or combinations thereof.
  • the ophthalmologically suitable compositions of the invention have a final pH of about 6 to about 10, from 6.5 to about 8, or of about 7.2.
  • compositions can also contain a pharmaceutically acceptable carrier.
  • Some of the ophthalmologically suitable compositions of the invention contain trehalose.
  • the trehalose can be present in a range of 2.5-5%.
  • Exemplary final concentrations of trehalose can be 2.5%, 3.0%, 3.5%, 4.0%, 4.5% or 5.0%.
  • One specific ophthalmologically suitable composition has a final concentration of 3.4% trehalose.
  • the ophthalmologically suitable compositions of the invention can be solutions, creams, pastes, ointments, or gels.
  • the ophthalmologically suitable compositions of the invention can also contain an opthalmoligically acceptable thickening agent, such as carboxymethylcellulose, dextran, sorbitol, mannitol, ethyl cellulose, hydroxytheyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidine, polyvinyl alcohol, carboxyvinyl polymer, carbopol, isopropyl myristate, petroleum jelly, mineral oil, lanolin, polyethylene glycol, propylene glycol, glycerin, glucose, sucrose, lactose, agar, alcohols, gums, waxes, or combinations thereof.
  • an opthalmoligically acceptable thickening agent such as carboxymethylcellulose, dextran, sorbitol, mannitol, ethyl cellulose,
  • a specific ophthalmologically suitable composition of the invention contains an opthalmoligically acceptable thickening agent at a final concentration of about 2.5%, 2%, 2.25%, 2.5%, 1.75%, 1.5%, 1.25%, 1.0%, 0.75%, 0.5%, and 0.25%.
  • the composition comprises the opthalmoligically acceptable thickening agent sodium carboxymethylcellulose at a final concentration of 0.25%.
  • compositions of the invention are suitable for application to the eye, eye-lid, eye margin, punctal plug or a contact lens.
  • compositions of the invention do not contain a bicyclic compound, e.g., dyphilline.
  • the ophthalmologically suitable compositions of the invention can also contain boric acid.
  • One exemplary ophthalmologically suitable composition of the invention has an osmolality of 180 mOsm/Kg or less and wherein the chlorine dioxide is present in a concentration of about 50-75 ppm.
  • composition of the invention contains the following components at about the following final concentrations:
  • This specific ophthalmologically suitable composition has an osmolality of about 145-155 mOsm/Kg.
  • ophthalmologically suitable compositions of the invention are aqueous compositions.
  • the invention also provides methods for treating microbial colonization or infection in or around the eye of a subject by applying the ophthalmologically suitable compositions of the invention to the colonized or infected area in an amount sufficient to treat a microbial colonization or infection in a subject.
  • Exemplary microbial colonizations include bacterial, fungal or yeast colonization or infection.
  • the ophthalmologically suitable compositions can be in the form of drops, solutions, creams, pastes, ointments, or gels. They can also be formulated into sustained-release carriers, such as sustained release polymers, liposomes or microcapsules.
  • the invention also provides methods of preventing or treating an infection of the ocular surface in a subject by applying a composition of the invention to an ocular surface in an amount sufficient to prevent or treat an infection of the ocular surface in the subject.
  • An exemplary infection of the ocular surface includes bacterial conjunctivitis.
  • the invention also provides a method for reducing the risk of infection in patients, including dry-eye patients, wearing contact lenses.
  • the invention also provides methods of reducing the risk of infection of the eye in an eye surgery patient by applying the compositions described herein to an eyelid or ocular surface prior to a surgical procedure in an amount sufficient to reduce the risk of infection in the eye of a surgical patient.
  • the composition is applied multiple times over a number of days preceding the surgery.
  • the invention also provides methods of reducing the risk of infection of the eye in a subject wearing a punctal plug by applying the compositions described herein to the eye surface, the eyelid margin, the eyelid or the punctal plugs or into the tear film in an amount sufficient to reduce the risk of infection in the eye of the subject wearing a punctal plug.
  • the invention also provides methods for treating or reducing the risk of infection in a subject by applying the topical composition described herein to the area that is infected or at risk of becoming infected in an amount sufficient to treat or reduce the risk of infection.
  • the invention also provides methods of reducing colonization or of treating an infection of the mucosal tissue or the epithelial tissue in a subject by applying the composition described herein to the mucosal tissue or the epithelial tissue in an amount sufficient to treat the infection in the subject.
  • the invention also provides a method of treating dry eye in a subject by applying the eye care composition described herein to the eye or eyelid in an amount sufficient to treat dry eye in the subject.
  • the invention also provides a method of increasing goblet cell density and mucosal epithelial membrane mucin expression in a subject by applying the eye care composition described herein to the eye in an amount sufficient to increase goblet cell density and mucosal epithelial membrane mucin expression. This increase can be determined using rose Bengal or other vital staining techniques. In dry eye, the ocular surface stains less with an increase in conjunctival goblet cell density and mucosal epithelial membrane mucin expression.
  • the invention also provides methods for sterilizing a surface by contacting the surface with the composition described herein, or incorporating within a surface the composition described herein, in an amount sufficient to sterilize the surface.
  • Exemplary surfaces include surfaces on a body, a medical instrument, or a medical device.
  • An exemplary medical device includes a contact lens.
  • kits for the treatment or prevention of a microbial infection comprising the compositions described herein and instruction for use.
  • the kits may further comprise an applicator.
  • compositions and methods for preventing microbial growth and treating microbial infections there exists a need for compositions and methods for preventing microbial growth and treating microbial infections.
  • compositions for preventing microbial growth in products for use in the eye or surrounding area In particular, the need exists for compositions that remain free of microbial growth for extended periods of time, i.e., compositions that contain a preservative that inhibit microbial growth and that do not irritate the area to which it is applied.
  • the compositions will contain an antimicrobial composition that will kill or retard the growth of microbes (e.g., a bactericidal or bacteriostatic composition).
  • the compositions are also useful for treating or preventing infection of, for example, the skin.
  • preparations of the invention are useful in treating or preventing infection on surfaces, medical devices, and medical instruments.
  • cleaning an eyelid is used herein to describe the act of significantly reducing the amount of dirt, debris, or bacteria, from an eyelid.
  • dry eye is known in the art as a condition of a subject that has a loss of water from the tear film due to either a decrease in tear production or an increase in tear film evaporation.
  • Tear production can decrease from lacrimal gland disease, including, but not limited to, that which occurs in Sjogren's syndrome, or from anything that decreases corneal sensation. Examples of conditions that decrease corneal sensation include, but are not limited to, diabetes, long-term contact lens wear, and corneal surgery, including LASIK eye surgery. Tear film evaporation can increase from meibomian gland dysfunction, that manifests itself by stenosis or closure of the meibomian gland orifices, or in the presence of large palpebral fissure widths.
  • Causes for large palpebral fissure width include, but are not limited to, normal biological variation and thyroid eye disease. Dry eye is often an age related disease, and may also be caused by a dietary deficiency of omega- 3 essential fatty acids. Dry eye is associated with bacterial overcolonization of the eyelids.
  • eyelid includes the tarsal conjunctival surface, both the interior and exterior surfaces of the eyelid, the eyelid margin, the glands in and around the eyelid margins, the hair follicles of the eyelid, the eyelashes, and the periocular skin surrounding the eye.
  • eye surface inflammatory disorder is intended to include disorders associated with eye surface inflammation. These disorders include dry eye, where ocular surface inflammation has been demonstrated, as well as both anterior and posterior blepharitis. In anterior blepharitis, the inflammation is centered around the eyelashes.
  • Posterior blepharitis or meibomitis is associated with inflammation of the tarsal and bulbar conjunctiva, and complicated by hordeolums and chalazions, and leads to meibomian gland dysfunction. Both anterior and posterior blepharitis are associated with bacterial overcolonization of the eyelids.
  • Animal models with combined dry eye and eye surface inflammatory disorder have been produced, and can be used to test the efficacy of the antimicrobial preparations provided herein.
  • a rabbit model for meibomianitis and meibomian gland dysfunction has been developed.
  • meibomian gland orifice closure results in the development of inflammation around the meibomian glands (i.e., meibomianitis), inflammation in the eyelids (blepharitis), inflammation in the conjunctiva (conjunctivitis) and in an increase in tear film osmolality and a decrease in the levels of corneal glycogen and conjunctival mucus- containing goblet cells characteristic of dry-eye surface disease.
  • eyelid disorder is defined as a disorder that results in inflammation of the eyelashes and/or eyelash follicles and/or eyelid margins, or inflammation of the lipid producing glands that are located in the eyelid, including meibomianitis and anterior blepharitis.
  • exemplary eyelid disorders include, but are not limited those caused by bacterial infection.
  • ocular disorder includes ocular surface disorders, disorders of the eyeball, periocular skin disorders, and eyelid disorders.
  • exemplary ocular disorders include, but are not limited to, dysfunctions of the tear film, inflammation of the eyelid margins due to bacterial infection, infections inside the eye known as endophthalmitis, and dry eye.
  • treatment is defined as prophylactic treatment (e.g., daily preventative use) or therapeutic treatment (e.g., a single treatment or a course of treatment) of a subject with or at risk for an ocular disorder, or with an ear or skin condition, that are associated with or exacerbated by infections or bacterial colonization.
  • preparation or antimicrobial preparation includes compositions comprising an oxidizing antimicrobial compound, for example, chlorine dioxide.
  • the preparation of the invention can be a solution, cream, paste, ointment, gel or the like.
  • preparations of the invention can be applied to, for example, the skin, eye, or eyelid.
  • compositions suitable for topical application preferably take the form of a drop, solution, ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • exemplary carriers which may be used include water, carboxymethylcellulose, petroleum jelly, mineral oil, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof.
  • the term "ophthalmologically suitable composition” is intended to mean that the composition is appropriate for application to the eye and the area around the eye. In certain embodiments, this means that the composition does not irritate or inflame the eye. Moreover, it is intended to mean that application to the eyelid or surrounding areas does not result in discomfort to the subject.
  • the term "activated chlorine dioxide” is intended to mean chlorine dioxide that has been produced in the presence of a strong acid thereby increasing the ability of the chlorine dioxide to be bactericidal or bacteriostatic.
  • the chlorine dioxide composition is contacted produced in a solution that has a pH of less than 6.8, 6.7, 6.6, 6.5, 6.4, 6.2, 6.1, 6.0, 5.9, 5.8, 5.5, 5.3, 5.1, 4.9, 4.7, 4.5 or lower.
  • the pH of the composition may ultimately be increased, the chlorine dioxide is activated once upon the pH of the solution being adjusted to a sufficiently acidic pH.
  • compositions that have extended utility once opened, i.e., that resist microbial growth are useful for the treatment of the eye.
  • the present invention provides compositions and methods, which decrease, e.g., significantly decrease, the number of microbes present in or around, for example, an eye, or in materials used in or around the eye.
  • the invention is directed to a preparation comprising an antibacterial concentration of activated chlorine dioxide, wherein the composition has an osmolality of less than 200 m ⁇ smol/kg.
  • the preparation may also contain a pharmaceutically acceptable carrier or water.
  • the preparation may be used as a preservative for materials used in conjunction with the eye such as eye drops or may be specifically formulated for the treatment of a particular disorder, e.g., an ocular disorder selected from blepharitis, dry eye, infectious conjunctivitis, an ear infection, or a skin infection.
  • the preparation may also be used to sterilize, for example, surgical instruments, medical indwelling devices, surfaces and the like.
  • the preparation may also be incorporated into the surface of medical devices for sustained release of the preparation.
  • preparation of the invention may be prepared in the form of drops, solution, paste, cream, foam, gel, ointment, or the like, or incorporated into sustained-release carriers such as sustained-release polymers, liposomes and microcapsules.
  • Chlorine dioxide can be produced with high efficiency by reducing sodium chlorate in a strong acid solution with a suitable reducing agent (for example, hydrogen peroxide, sulfur dioxide, or hydrochloric acid): 2ClO 3 " + 2Cl " + 4H + ⁇ 2ClO 2 + Cl 2 + 2H 2 O
  • a suitable reducing agent for example, hydrogen peroxide, sulfur dioxide, or hydrochloric acid
  • chlorine dioxide can be made by one of three methods using sodium chlorite: The sodium chlorite-chlorine gas method (2 NaClO 2 + Cl 2 - ⁇ 2 ClO 2 + 2 NaCl); the sodium chlorite-hypochlorite method (2 NaClO 2 + 2 HCl + NaOCl ⁇ 2 ClO 2 + 3 NaCl + H 2 O); or the sodium chlorite-hydrochloric acid method (5 NaClO 2 + 4 HCl ⁇ 5 NaCl + 4 ClO 2 ). Finally, chlorine dioxide can be produced by electrolysis of a chlorite solution (NaClO 2 + H 2 O ⁇ ClO 2 + NaOH + 1/2 H 2 ).
  • Preparations of the invention comprise between about 25-200 ppm of chlorine dioxide, about 50-150 ppm of chlorine dioxide, about 50-100 ppm of chlorine dioxide, or about 50-75 ppm of chlorine dioxide. For treatment of infection, higher values may be used.
  • these chemical reactions take place in an acidic environment in order to activate the chlorine dioxide.
  • the antimicrobial preparation is an aqueous solution containing chlorine dioxide as described herein.
  • the solutions of the invention can have an osmolality of, for example, about 180 mOsm/Kg, about 175 mOsm/Kg or less, about 170 mOsm/Kg, about 165 mOsm/Kg or less, about 160 mOsm/Kg or less, or about 155 mOsm/Kg or less.
  • An exemplary preparation of the invention is a preparation having an osmolality of 165 mOsm/Kg or less and a chlorine dioxide concentration of about 50- 75 ppm.
  • the preparations may further include buffers, solubilizers, viscosity increasing agents, preservatives, anti-inflammatory agents and salts.
  • the invention provides an ophthalmologically suitable composition comprising activated chlorine dioxide, wherein the osmolality of the composition is less than 180 mOsm/Kg.
  • the eye drop includes a balance of electrolytes found in natural tear fluid required for ocular surface maintenance, function and repair. These electrolytes are present in amounts and proportions sufficient to maintain or restore conjunctival goblet cells and corneal glycogen, thereby maintaining mucus-mediated lubrication and the potential for normal healing.
  • compositions of the invention include, in addition to chlorine dioxide, a balance of electrolytes naturally found in tear fluid. These electrolytes principally include major amounts of sodium and chloride, and lesser amounts of potassium and bicarbonate.
  • the ophthalmologically suitable compositions may also contain other naturally-occurring elements of the tear fluid, such as proteins, enzymes, lipids and metabolites as described in U.S. Patent No. 4,91 1,933.
  • the potassium is present at a concentration of about 22.0 to 43.0 mM/1
  • the bicarbonate is present at a concentration of about 29.0 to 50.0 mM/1
  • the sodium is present at a concentration of about 130.0 to 140.0 mM/1
  • the chloride is present at a concentration of about 118.0 to 136.5 mM/1
  • the electrolyte components can be diluted to create hypotonic formulations where the ratios between the electrolyte concentrations remain unchanged.
  • the ophthalmologically suitable compositions can further optionally include calcium, magnesium and phosphate.
  • the calcium is preferably present at a concentration of about 0.5 to 2.0 mM/1
  • the magnesium is preferably present at a concentration of about 0.3 to 1. 1 mM/1
  • the phosphate is preferably present at a concentration of about 0.8 to 2.2 mM/1.
  • the electrolyte components can be diluted to create hypotonic formulations where the ratios between the electrolyte concentrations remain unchanged.
  • the final pH of the ophthalmologically suitable compositions generally ranges from about 7.0 to 8. 0, as measured by, for example, a Fisher pH Accumet Model 600.
  • this pH range need not be rigidly adhered to, and it may be desirable to alter pH outside of this range, for instance, to improve ophthalmic drug penetration through the ocular surface.
  • those skilled in the art may employ other pH ranges.
  • compositions of the invention can be applied to the ocular surface by various methods known in the art.
  • the compositions can be applied topically to the ocular surface as eye drops or ointments.
  • the preparation can also be applied using an eye cup so that the eye is bathed.
  • the compositions can also be applied using a continuous or near continuous infusion device for ocular surface irrigation and/or wetting and/or drug delivery.
  • the compositions can also be applied by release from a sustained-release carrier such as a sustained-release polymer, a liposome or a microcapsule.
  • the compositions may also be applied by devices that spray solutions as required onto the surface of the eye.
  • the invention is further directed to methods of using the compositions described above to treat a subject, e.g., a subject having or at risk of having an infection, e.g., an infection of the eye or skin.
  • the method comprises the step of applying the ophthalmologically suitable compositions described herein to the site of the infection, or site where an infection is likely to occur, or the site from which an infection might originate, for a time and under conditions effective for reducing the amount of bacteria present.
  • the time and conditions selected result in an at least about 1 log reduction in colony-forming units of the infecting bacteria after one minute of exposure to the antimicrobial preparation.
  • the application of the ophthalmologically suitable composition for one minute results in an at least about 2, 3, 4 or 5 log reduction in colony-forming units.
  • the invention also provides methods of treating ocular disorders such as blepharitis, dry eye, eye inflammatory disorders, infectious conjunctivitis, and other ocular disorders that result from or are complicated by bacterial colonization or infection of the eye or surrounding tissue, by applying the ophthalmologically suitable compositions provided herein to the eye and/or surrounding tissue of a subject.
  • ocular disorders such as blepharitis, dry eye, eye inflammatory disorders, infectious conjunctivitis, and other ocular disorders that result from or are complicated by bacterial colonization or infection of the eye or surrounding tissue
  • the invention also provides methods of treating infection of the ocular surface by applying the ophthalmologically suitable compositions provided herein to the eye of a subject.
  • Exemplary infections that can be treated with the antimicrobial preparations provided herein include conjunctivitis, e.g., infectious conjunctivitis and corneal ulcers.
  • the invention also provides methods of preventing an eye infection in a subject having an eye surgery or procedure. These methods would comprise applying an ophthalmologically suitable composition described herein to the eye over a number of days preceding the surgery or procedure to reduce or eliminate the risk of developing an infection during the surgery or procedure. Exemplary procedures include cataract or LASIK surgery.
  • the invention also provides methods of maintaining low bacterial colony counts on punctal plugs that have been placed in patients for treatment. Exemplary punctal plugs include those manufactured by Odyssey Medical (Memphis, TN), and Eagle Vision (Memphis, TN).
  • compositions set forth herein can be by any one of a number of art recognized methods.
  • application can be by an applicator, such as a Qtip or pad, by drops from a dropper or bottle, or using a finger or fingers.
  • the ophthalmologically suitable compositions of the invention may be applied one or more times per day, and may be left in place as long as needed, depending on the intended indication.
  • the number of days which a subject applies the ophthalmologically suitable composition, and the duration of the application, will depend on the intent of treatment or on the location and severity infection, and efficacy of the preparations on a given infection.
  • the ophthalmologically suitable composition may be applied for a period of 30 seconds, 45 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, or longer.
  • the ophthalmologically suitable composition can be applied by release from a sustained release carrier such as a sustained-release polymer, a liposome or a microcapsule.
  • the ordinary skilled physician would be able to effectively prescribe a treatment regimen that will be effective in treating or preventing an infection in an individual.
  • the methods described above may further include a rinsing step after a recommended period of exposure.
  • This step preferably comprises a simple water rinse.
  • the ophthalmologically suitable composition may be rinsed from the area to which it was applied with ample water after application, e.g., with a hand, finger or any moist pad or cloth suitable for this purpose.
  • the invention provides disinfecting a surface.
  • Exemplary surfaces include those on medical instruments, in medical facilities, on medical devices, and those in a home, e.g., in a kitchen or bathroom.
  • the invention includes a kit comprising the compositions of the invention, e.g., a kit for the treatment of an infection, e.g., an ocular infection, an ocular disorder, eyelid hygiene.
  • the kits optionally include an applicator.
  • the composition can be in the form of drops, solution, paste, cream, foam, gel, or ointment, or the like, when included in the kits of the invention.
  • the kit may optionally be packaged with instructions for use.
  • the kit may optionally contain a dispenser or applicator, e.g., a sponge, to apply the ophthalmologically suitable compositions of the invention to the infected area of a subject.
  • Example 1 Formulation and Efficacy of Compositions Containing Activated Chlorine Dioxide
  • Candida albicans A TCC 10231 5. Aspergillus niger, ATCC 16404
  • the log reduction was determined by the plate count method after 7 14, 21 and 28 days by diluting in DEB from 10 ' to 10 "4 for bacteria/yeast and 10 " l to 10 " for mold.
  • the plates were then poured with the appropriate media and incubated.
  • Bacterial plates were poured with SCDA and incubated at 32.5 ⁇ 2 .5°C.
  • Yeast/mold plates were poured with SCDA and incubated at 22.5 ⁇ 2.5°C.
  • the initial antimicrobial effectiveness data was reviewed before any further testing for antimicrobial effectiveness was conducted. Only formulas that had met the acceptance criteria at the initial testing were followed beyond the initial testing.
  • Electrolytes and buffers are adjusted appropriately to obtain various osmolalities between 130 and 200 m ⁇ sm/kg.
  • Formulations are effective with or without boric acid and/or hydrochloric acid for pH adjustment.
  • Solution C3 had an osmolality of 132 mOsm/kg. It was prepared and aliquoted into 2 dram LDPE bottles. These bottles were placed at 40°C/NMT 25% RH for 3 months. The pH, osmolality, viscosity and chlorine dioxide testing was performed at 3 month timepoint. Sample C3 was tested at 2.5 months for Preservative Efficacy. Table 1 shows the results from the testing for pH, osmolality, viscosity and Chlorine Dioxide. Table 2 shows the results from the Preservative Efficacy testing.
  • Example 2 Formulation and Efficacy of Compositions Containing Activated Chlorine Dioxide and Trehalose
  • An exemplary composition of the invention is described in this example and data demonstrating the efficacy of this composition is also provided.
  • a solution was made by measuring 800.2 g of water into a 1000 mL bottle. A stir bar was added to the solution and the beaker was placed on a hot plate. The solution was heated to 70 °C and 5.02 g of Sodium Carboxymethylcellulose was slowly added. The solution was mixed on a hot plate for 30 minutes, removed from heat and allowed to cool to room temperature to dissolve the CMC. The solution was diluted to 1000.1 g with water. The solution was autoclaved at 121 °C for 50 minutes. This solution was termed "Phase I".
  • the solution was made by measuring 413.98 g of water into a 600 mL beaker.
  • the solution was prepared by mixing 450.03 g of Phase I and 450.06 g of Phase II in a 1000 mL bottle.
  • the pH of the solution was found to be 7.44.
  • C4 was tested for the ability to kill S. aureus, P. aeruginosa, E. coli, C. albicans, and A. Niger. As indicated in Table 3 below, C4 effectively kills all of the microorganisms.
  • Example 3 Formulation of Compositions Containing 1% CMC exemplary gel composition was prepared by increasing the CMC content hown below for composition C5.
  • composition C6 An exemplary composition was prepared by including dyphilline as shown below for composition C6.
  • Example 5 Efficacy of the Compositions of Examples 3 and 4
  • C5 and C6 were tested for their ability to kill S. aureus, P. aeruginosa, E. coli, C. albicans, and A. Niger as descirbed above. As indicated in Table 4 below, C5 and C6 effectively kill all of the microorganisms.

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Abstract

La présente invention concerne des préparations comprenant du dioxyde de chlore activé qui améliore l'effet antibactérien de la préparation d'agent antimicrobien oxydant. L'invention peut être utilisée en particulier comme préparation de soin oculaire, par exemple une goutte oculaire. L'invention comprend en outre des procédés pour réduire la colonisation bactérienne et traiter une infection.
EP10733709A 2009-01-20 2010-01-19 Procédés et compositions pour le traitement et la prévention d'infections Withdrawn EP2389069A1 (fr)

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US6200557B1 (en) * 1993-07-06 2001-03-13 Perry A. Ratcliff Method of treating HIV by a topical composition
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AR031135A1 (es) * 2000-10-10 2003-09-10 Upjohn Co Composiciones de antibiotico topico para el tratamiento de infecciones oculares
US20080020064A1 (en) * 2006-07-21 2008-01-24 Advanced Vision Research Methods and compositions for the treatment of infection or infectious colonization of the eyelid, ocular surface, skin or ear

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