+

US20130137651A1 - Gel useful for the delivery of ophthalmic drugs - Google Patents

Gel useful for the delivery of ophthalmic drugs Download PDF

Info

Publication number
US20130137651A1
US20130137651A1 US13/749,790 US201313749790A US2013137651A1 US 20130137651 A1 US20130137651 A1 US 20130137651A1 US 201313749790 A US201313749790 A US 201313749790A US 2013137651 A1 US2013137651 A1 US 2013137651A1
Authority
US
United States
Prior art keywords
carnitine
solid powder
gel
powder
sodium
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.)
Abandoned
Application number
US13/749,790
Inventor
Antonio Longo
Mosè Santaniello
Nicola Pescosolido
Aleardo Koverech
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.)
Sigma Tau Industrie Farmaceutiche Riunite SpA
Original Assignee
Sigma Tau Industrie Farmaceutiche Riunite SpA
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 Sigma Tau Industrie Farmaceutiche Riunite SpA filed Critical Sigma Tau Industrie Farmaceutiche Riunite SpA
Priority to US13/749,790 priority Critical patent/US20130137651A1/en
Assigned to SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P.A. reassignment SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KOVERECH, ALEARDO, LONGO, ANTONIO, PESCOSOLIDO, NICOLA, SANTANIELLO, MOSE
Publication of US20130137651A1 publication Critical patent/US20130137651A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K47/08—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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • the present invention relates to a physiological supplement or medicament in the form of a solid powder which comprises a mixture of: a polymer which forms a gel, a buffer; a saccharide and one or more active ingredients useful for treating diseases of the eyes, in which said powder once is reconstituted with a suitable amount of water, or a liquid solution, provides a gel useful for the prevention or treatment of the eyes.
  • Non limiting examples of diseases of the eye are cystinosys, dry eye syndrome, corneal oedema and diseases of the eyes due to ultraviolet radiation.
  • Cystinosys is a genetic metabolic disease that causes an amino acid, cystine, to accumulate in various organs of the body. Cystine crystals accumulate in the kidneys, eyes, liver, muscles, pancreas, brain and white blood cells. Without specific treatment, children with cystinosys develop end stage kidney failure at approximately age nine.
  • Cystinosis also causes complications in other organs of the body. The complications include muscle wasting, difficulty swallowing, diabetes, and hypothyroidism. It is estimated that at least 2,000 individuals worldwide have cystinosys, thought exact numbers are difficult to obtain because the disease is often undiagnosed and/or misdiagnosed.
  • the damage to the kidneys and other organs is thought to be due to accumulation of cystine inside the cells of various body tissues. This chemical also accumulates in the cornea and iris. After 10 to 20 years, the corneas of some patients become so packed with crystals that the surfaces may become irregular, occasionally causing small, painful breaks.
  • Dry eye syndrome is characterised by a quantitative (hypolacrimation) and/or qualitative (dyslacrimation) impairment of the tear film of multifactorial origin which may or may not cause clinically significant damage to the eye surface.
  • the prevalence of dry eye syndrome ranges from 10 to 40% in the adult population and there is a highly significant correlation with age.
  • Oedema or swelling of the cornea occurs when the cornea is unable to keep itself clear and fluid begins to accumulate within it.
  • the inside lining of the cornea is responsible of keeping it clear, and if this layer is damaged symptoms of corneal oedema may occur.
  • causes of corneal oedema include disorders of the inside layer of the cornea such as Fuchs' endothelial dystrophy; eye surgery, such as cataract surgery; eye trauma; acute glaucoma with very high eye pressure; contact lens; infections.
  • Treatment of corneal oedema depends on its cause. Mild oedema can be treated with hypertonic eye drops and ointments. This draws fluid out of the cornea and into the tears, and helps to clear the cornea. More severe oedema, especially with blister (bullae) formation, may require corneal transplant to correct.
  • Ultra-violet radiation has long been recognized as a factor in the development of cutaneous cancer, aging of the skin, and mutagenic changes, it is only within the last decade or less that ultra-violet radiation has been universally recognized as a causative factor in ocular pathogenesis.
  • the eye has evolved into a sophisticated organ having neurophysiologic responses to photons in a certain portion of the electromagnetic spectrum that provides a constant detailed map of the immediate environment.
  • the action spectrum for these responses lie primarily within the 400-700 NM wavelength range, which has been labeled the visible spectrum or “Light”.
  • Age related cataract pterygium
  • Macular Degeneration such as age related maculopathy (ARM), non age related maculopathy (nARM), age related macular degeneration (AMD); attinic photokeratitis and conjunctivitis.
  • a drug to be applied topically on the eye is more effective if said drug remains in the eye in a time sufficient to exert its preventive or curative function.
  • various ophthalmic vehicles have been developed. Examples of such ophthalmic vehicles include various inserts, ointments, suspensions and gels.
  • the ophthalmic vehicles known in the art have some drawbacks. For example, the use of ointments often causes blurred vision. Also, insert is not particularly popular among patients due to its low patient compliance.
  • CAP cellulose acetophthalate
  • Rozier et al. Int. J. Pharm. (1989), 57: 163-168, discloses an ion-activated gelling vehicle with a trademark of Gelrite®.
  • Rozier et al.'s gelling vehicle has the disadvantages of being converted into gel in the presence of mono- or divalent cations.
  • Kumar et al., J. Ocular Pharmacol. (1994), 10: 47-56 discloses an ocular drug delivery system based on a combination of Carbopol and methylcellulose. The sol-gel transition of the combination occurs primarily due to an increase in pH because of the presence of Carbopol.
  • Kumar et al., J. Pharm. Sci. (1995), 84: 344-348 (1995) discloses yet another ocular drug delivery system containing Carbopol and hydroxypropylmethylcellulose. In both systems, a viscosity-enhancing polymer is added to achieve a reduction in Carbopol concentration without compromising the in situ gelling properties as well as overall rheological behaviors.
  • Viegas et al.'s U.S. Pat. No. 5,593,683 discloses a method for making thermo reversible gels for drug or diagnostic agent delivery.
  • the gels contain a pharmaceutical agent, a surfactant, and a polyalkylene polyether.
  • the combined total amount of the surfactant and the polyalkylene polyether does not exceed about 10% by weight.
  • a solid powder which comprises a mixture of a natural or synthetic polymer which forms a gel, a buffer, a saccharide, and a drug useful for the treatment of diseases of the eyes, in which said powder, once is reconstituted with a solution provides a gel suitable for ophthalmic administration.
  • the gel according to the present invention remains adherent to the eye, lengthens the retention time of instilled ophthalmic drug in the eye, and enhances the bioavailability of said ophthalmic drug.
  • the powder according to the present invention once reconstituted with water or a solution, provides a gel suitable for ophthalmic use.
  • a gel useful for preparing a medicament for the treatment of diseases of the eyes, which comprises a mixture of:
  • Preferred active ingredients are those which are not stable in water or in solution.
  • the powder so obtained before the use needs to be reconstituted with water or a solution.
  • physiological supplement or medicament for ophthalmic use which comprises the powder or the gel of the invention and one or more drugs useful for the treatment of diseases of the eyes; and optionally one or more excipients and/or regulators of the osmotic pressure ophthalmologically acceptable.
  • physiological supplement or medicament for ophthalmic use which comprises the powder or the gel of the invention and as a drug (as active ingredient) cysteamine.
  • physiological supplement or medicament for ophthalmic use which comprises the powder or the gel of the invention and the following components:
  • This physiological supplement or medicament is particularly useful for the treatment of dry eye syndrome.
  • physiological supplement or medicament for ophthalmic use which comprises the powder or the gel of the invention and the following components;
  • sodium hyaluronate at a dose of 0.05-1.5%, a preferred dose is 0.2%;
  • vitamin E at a dose of 0.05-1.0%, a preferred dose is 0.2%;
  • a preferred dose is 9 mg/L.
  • This physiological supplement or medicament is particularly useful for the treatment of corneal oedema.
  • physiological supplement or medicament for ophthalmic use which comprises the powder or the gel of the invention and the following components;
  • a preferred dose is 1.02 mg/L;
  • manganese at a dose of 0.01-0.1 mg/L a preferred dose is 0.051 mg/L;
  • a preferred dose is 30 mg/L;
  • a preferred dose is 9 mg/L.
  • This physiological supplement or medicament is particularly useful for the treatment of eye diseases due to ultraviolet radiation.
  • the physiological supplements or medicaments of the invention may further comprise one or more of the following active ingredients: antioxidants, vitamins, Borage oil;
  • the powder or the gel of the invention when combined with one or more ophthalmic drugs, is useful for preparing a medicament for the treatment of diseases of the eye.
  • kits comprising the powder of the invention in admixture with one or more active ingredients (useful in the ophthalmic field) and, separately, in the same or in a different container/vial, water or a liquid solution suitable for obtaining the gel of the invention.
  • kit comprising:
  • the expert in container for ophthalmic use can easily suggest suitable containers which contains, for example, the gel mixed with one or more drugs; or a powder and separately (in the same container) a liquid; or 2 different powders and a liquid; for single or multiple applications.
  • suitable containers which contains, for example, the gel mixed with one or more drugs; or a powder and separately (in the same container) a liquid; or 2 different powders and a liquid; for single or multiple applications.
  • suitable containers which contains, for example, the gel mixed with one or more drugs; or a powder and separately (in the same container) a liquid; or 2 different powders and a liquid; for single or multiple applications.
  • Different containers/vials are also included in the present invention.
  • compositions that are not give rise to toxic or side effects.
  • Non-limiting examples of such salts are: chloride, bromide, orotate, aspartate, acid aspartate, acid citrate, magnesium citrate, phosphate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulphate, acid sulphate, glucose phosphate, tartrate and acid tartrate, glycerophosphate, mucate, magnesium tartrate, 2-amino-ethanesulphonate, methanesulphonate, choline tartrate, trichloroacetate, and trifluoroacetate.
  • FIG. 1 shows shear stress and viscosity vs shear rates of the gel prepared in EXAMPLE 1.
  • the gel resisted the initial rotary motion and a sudden increase in shear stress was observed at higher shear rate.
  • the gel began to flow after shear stress reached its yield point. This system is a Newtonian flow of the pseudoplastic type with no hysteresis.
  • FIG. 2 shows shear stress and viscosity vs shear rates of the gel prepared in EXAMPLE 2.
  • the gel resisted the initial rotary motion and a sudden increase in shear stress was observed at higher shear rate.
  • the gel began to flow after shear stress reached its yield point. This system is a Newtonian flow of the pseudoplastic type with no hysteresis.
  • FIG. 3 shows shear stress and viscosity vs shear rates of the gel prepared in EXAMPLE 3. It can be observed with this gel that shear stress increases linearly with an increase in shear rate. This gelatinous system presents typical non-Newtonian flow behavior.
  • FIG. 4 shows shear stress and viscosity vs shear rates of the gel prepared in EXAMPLE 4.
  • the gel resisted the initial rotary motion and a sudden increase in shear stress was observed at higher shear rate.
  • the gel began to flow after shear stress reached its yield point. This system is a Newtonian flow of the pseudoplastic type with no hysteresis.
  • FIG. 5 shows the cumulative amount of cysteamine released vs time profiles for gel prepared as in EXAMPLE 1. The drug released about 42% into the medium after 30 min and then in gradual fashion. Approximately 96% of the cysteamine was released from the gel after 6 h.
  • FIG. 6 shows the cumulative amount of cysteamine released vs time profiles for gel prepared as in EXAMPLE 2. The drug released about 46% into the medium after 30 min and then in gradual fashion. Approximately 98% of the cysteamine was released from the gel after 6 h.
  • Carbopol 974P NF Noveon
  • cysteamine and all other chemicals, including tartaric acid and benzalconium chloride, were purchased from Sigma and were used as received.
  • the gelatinous system thus obtained was divided into fractions of 3 mL in 10-mL vials. Said vials were lyophilized for 24 h and a white solid was obtained.
  • the gelatinous system thus obtained was divided into fractions of 3 mL in 10-mL vials. Said vials were lyophilized for 24 h and a white solid was obtained.
  • the gelatinous system thus obtained was divided into fractions of 3 mL in 10-mL vials. Said vials were lyophilized for 24 h and a white solid was obtained.
  • the reo logical studies were carried out with a rotational viscometer of the concentric cylinder type (Viscometer TV-10 Toky Sangyo equipped with a small sample adapter and rotor type M3).
  • the viscosity and shear stress of the samples were measured at various rates at 25° C.
  • the temperature was maintained within +/0.1° C. by a recirculating bath connected to the viscometer.
  • the samples were equilibrated for five minutes to reach the running temperature prior to each measurement.
  • the HPLC chromatographic system composed of a pump (Waters 600); and autosampler (Waters 717); a UV detector (Waters 486) and integrator (Waters Empower 2).
  • the flow rate and UV wavelength were 0.8 mL/min and 205 nm, respectively.
  • the drug concentrations were determined by measuring the peak area in comparison with the peak area of known standards.
  • Carbopol® is a registered trademark of Noveon, Inc. (formerly B.F. Goodrich Co.) for a family of polymers that are used as thickeners, suspending agents and stabilizers.
  • L-carnitine and its alkanoyl derivatives are known compounds, the reparation process for which is described in U.S. Pat. No. 4,254,053.
  • 3-Hydroxykynurenine 0-3-DL-glucoside is a product sold by Sigma-Aldrich, catalogue 2006; product code n° H 1771.
  • the physiological supplement or medicament according to the present invention may be bought with or without medical prescription.
  • physiological supplements or medicaments according to the present invention are composed of active ingredients which are familiar to operators in the medical field and already in use in clinical practice, and their pharmacotoxicological profiles are known.
  • composition according to the present invention In the following are reported non limiting examples of composition according to the present invention.
  • the powder or the gel of the invention and cysteamine is particularly useful for the treatment of cystinosis.
  • This physiological supplement or medicament is particularly useful for the treatment of dry eye syndrome.
  • This physiological supplement or medicament is particularly useful for the treatment of corneal oedema.
  • This physiological supplement or medicament is particularly useful for the treatment of eye diseases due to ultraviolet radiation.
  • This physiological supplement or medicament is particularly useful for the treatment of eye diseases due to ultraviolet radiation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Ophthalmology & Optometry (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a solid powder composed of a mixture of a natural or a synthetic polymer which forms a gel, a buffer, such as an hydroxyacid or a dicarboxyacid, a saccharide, one or more drugs useful for the treatment of diseases of the eyes and optionally one or more excipients and/or regulators of the osmotic pressure ophthalmologically acceptable.

Description

  • This application is a divisional application of U.S. Ser. No. 12/517,445 filed on Jun. 16, 2009, which is a 371 of PCT/EP2007/062929 filed on Nov. 28, 2007, which claims priority to and the benefit of European Patent Application No. 06126981.7 filed on Dec. 22, 2006, the contents of each of which are incorporated herein by reference in their entirety.
  • The present invention relates to a physiological supplement or medicament in the form of a solid powder which comprises a mixture of: a polymer which forms a gel, a buffer; a saccharide and one or more active ingredients useful for treating diseases of the eyes, in which said powder once is reconstituted with a suitable amount of water, or a liquid solution, provides a gel useful for the prevention or treatment of the eyes.
  • Non limiting examples of diseases of the eye are cystinosys, dry eye syndrome, corneal oedema and diseases of the eyes due to ultraviolet radiation.
  • Cystinosys is a genetic metabolic disease that causes an amino acid, cystine, to accumulate in various organs of the body. Cystine crystals accumulate in the kidneys, eyes, liver, muscles, pancreas, brain and white blood cells. Without specific treatment, children with cystinosys develop end stage kidney failure at approximately age nine.
  • Cystinosis also causes complications in other organs of the body. The complications include muscle wasting, difficulty swallowing, diabetes, and hypothyroidism. It is estimated that at least 2,000 individuals worldwide have cystinosys, thought exact numbers are difficult to obtain because the disease is often undiagnosed and/or misdiagnosed.
  • The damage to the kidneys and other organs is thought to be due to accumulation of cystine inside the cells of various body tissues. This chemical also accumulates in the cornea and iris. After 10 to 20 years, the corneas of some patients become so packed with crystals that the surfaces may become irregular, occasionally causing small, painful breaks.
  • Treatment with cysteamine eye drops dissolves corneal cystine crystals and prevents damages of the eyes (N. Eng. J. Med. 347, 111-121; 2002).
  • Frequent instillation of concentrated solutions of cysteamine is necessary in order to achieve the desired therapeutic effects.
  • Dry eye syndrome is characterised by a quantitative (hypolacrimation) and/or qualitative (dyslacrimation) impairment of the tear film of multifactorial origin which may or may not cause clinically significant damage to the eye surface. The prevalence of dry eye syndrome ranges from 10 to 40% in the adult population and there is a highly significant correlation with age.
  • Oedema or swelling of the cornea occurs when the cornea is unable to keep itself clear and fluid begins to accumulate within it. The inside lining of the cornea is responsible of keeping it clear, and if this layer is damaged symptoms of corneal oedema may occur.
  • Causes of corneal oedema include disorders of the inside layer of the cornea such as Fuchs' endothelial dystrophy; eye surgery, such as cataract surgery; eye trauma; acute glaucoma with very high eye pressure; contact lens; infections.
  • Treatment of corneal oedema depends on its cause. Mild oedema can be treated with hypertonic eye drops and ointments. This draws fluid out of the cornea and into the tears, and helps to clear the cornea. More severe oedema, especially with blister (bullae) formation, may require corneal transplant to correct.
  • Ultra-violet radiation has long been recognized as a factor in the development of cutaneous cancer, aging of the skin, and mutagenic changes, it is only within the last decade or less that ultra-violet radiation has been universally recognized as a causative factor in ocular pathogenesis.
  • In humans, the eye has evolved into a sophisticated organ having neurophysiologic responses to photons in a certain portion of the electromagnetic spectrum that provides a constant detailed map of the immediate environment. The action spectrum for these responses lie primarily within the 400-700 NM wavelength range, which has been labeled the visible spectrum or “Light”.
  • Because solar UV radiation is present during most of the daylight hours, the eye may be exposed daily to some amount of solar ultraviolet radiation throughout life.
  • Diseases of the eye due to ultraviolet radiation include age related cataract; pterygium; Macular Degeneration such as age related maculopathy (ARM), non age related maculopathy (nARM), age related macular degeneration (AMD); attinic photokeratitis and conjunctivitis.
  • Most of the conventional ophthalmic drug delivery systems encounter great problems due to unique physiological conditions of the eye, i.e., when a conventional liquid ophthalmic formulation is applied to the eye, upon instillation, it is immediately eliminated from the pre corneal area of the eye because of lacrimal secretion and nasolacrimal drainage. As a result, only 1-10% of the ophthalmic drugs can be utilized by patients and a frequent instillation of concentrated solutions is necessary in order to achieve the desired therapeutic effects.
  • A drug to be applied topically on the eye is more effective if said drug remains in the eye in a time sufficient to exert its preventive or curative function. To lengthen the retention time of instilled ophthalmic drug in the eye and to enhance the bioavailability of the ophthalmic drug, various ophthalmic vehicles have been developed. Examples of such ophthalmic vehicles include various inserts, ointments, suspensions and gels. The ophthalmic vehicles known in the art have some drawbacks. For example, the use of ointments often causes blurred vision. Also, insert is not particularly popular among patients due to its low patient compliance.
  • Previous uses of gel for ophthalmic use are already known.
  • Gurny et al, J. Contr. Release (1985), 2:353-361, discloses an ocular drug delivery system which includes cellulose acetophthalate (CAP) latex and Carbopol solution.
  • Rozier et al., Int. J. Pharm. (1989), 57: 163-168, discloses an ion-activated gelling vehicle with a trademark of Gelrite®. However, Rozier et al.'s gelling vehicle has the disadvantages of being converted into gel in the presence of mono- or divalent cations.
  • Joshi et al.'s U.S. Pat. No. 5,252,318 discloses reversibly gelling aqueous compositions which contain at least one pH-sensitive reversibly gelling polymer (such as carboxy vinyl linear or branched or cross-linked polymers of the monomers) and at least one temperature-sensitive reversibly gelling polymer (such as alkylcellulose, hydroxyalkyl cellulose, block copolymers of polyoxyethylene and polyoxypropylene, and tetrafunctional block polymers of polyoxyethylene and polyoxypropylene and ethylenediamine). Joshi et al.'s compositions exhibit significant changes in viscosity in response to substantially simultaneous changes in both temperature and pH.
  • Kumar et al., J. Ocular Pharmacol. (1994), 10: 47-56, discloses an ocular drug delivery system based on a combination of Carbopol and methylcellulose. The sol-gel transition of the combination occurs primarily due to an increase in pH because of the presence of Carbopol. Kumar et al., J. Pharm. Sci. (1995), 84: 344-348 (1995), discloses yet another ocular drug delivery system containing Carbopol and hydroxypropylmethylcellulose. In both systems, a viscosity-enhancing polymer is added to achieve a reduction in Carbopol concentration without compromising the in situ gelling properties as well as overall rheological behaviors.
  • Finkenaur et al.'s U.S. Pat. No. 5,427,778 discloses gel formulations containing a polypeptide growth factor and a water soluble, pharmaceutically or ophthalmically compatible polymeric material for providing viscosity within various ranges determined by the application of the gel. Both Carbopol gels and Pluronic gels, respectively, are disclosed in the patent. Pluronic is the trademark for BASF's polyoxyethylene-polyoxypropylene block copolymers.
  • Viegas et al.'s U.S. Pat. No. 5,593,683 discloses a method for making thermo reversible gels for drug or diagnostic agent delivery. The gels contain a pharmaceutical agent, a surfactant, and a polyalkylene polyether. The combined total amount of the surfactant and the polyalkylene polyether does not exceed about 10% by weight.
  • In the ophthalmologic field there is still a perceived need to have new vehicles useful for preparing medicaments for treating diseases of the eyes, not endowed with the drawbacks of the products known in the art.
  • It has now been found that a solid powder which comprises a mixture of a natural or synthetic polymer which forms a gel, a buffer, a saccharide, and a drug useful for the treatment of diseases of the eyes, in which said powder, once is reconstituted with a solution provides a gel suitable for ophthalmic administration.
  • The powder according to the present invention, respect to the gel present on the market presents the following advantages:
      • (a) is useful for preparing composition for the delivery of ophthalmic drugs which are not stable in solution;
      • (b) may not contain irritant preservatives.
  • In fact, it is well known that the eye drops and the gel for ophthalmic use present on the market contain preservative to avoid microbial contamination and said preservatives are irritant for the eyes (J. Am. Coli. Toxicol 8, 589-625; 1989).
  • The gel according to the present invention remains adherent to the eye, lengthens the retention time of instilled ophthalmic drug in the eye, and enhances the bioavailability of said ophthalmic drug.
  • It is therefore an object of the present invention a solid powder which comprises a mixture of:
      • a) a natural or synthetic polymers which forms a gel, an example of said polymer is a carboxy vinyl polymer such as Carbopol;
      • b) a buffer, such as an hydroxyacid or a dicarboxylic acid selected from the group comprising phosphate, boric acetate, citrate, lactate, tartrate, maleate, succinate or fumarate;
      • c) a saccharide, selected from the group comprising glucose, fructose, mannitol, sorbitol, lactose, trehalose or maltose; and optionally
      • d) one or more drugs useful for the treatment of diseases of the eyes.
  • The powder according to the present invention once reconstituted with water or a solution, provides a gel suitable for ophthalmic use.
  • It is a further object of the present invention a gel, useful for preparing a medicament for the treatment of diseases of the eyes, which comprises a mixture of:
      • a) a natural or synthetic polymers which forms a gel, an example of said polymer is a carboxy vinyl polymer such as Carbopol;
      • b) a buffer, such as an hydroxyacid or a dicarboxylic acid selected from the group comprising phosphate, boric acetate, citrate, lactate, tartrate, maleate, succinate or fumarate;
      • c) a saccharide, selected from the group comprising glucose, fructose, mannitol, sorbitol, lactose, trehalose or maltose; and
      • d) one or more drugs useful for the treatment of diseases of the eyes. A non limiting example of said drugs is: cysteamine; pilocarpine; epinephrine; tetracycline; phenylephrine; eserine; timolo; L-carnitine and/or an alkanoyl L-carnitine selected from the group comprising: acetyl, propionyl, valeryl, isovaleryl, butyryl and isobutyryl L-carnitine, or an opthalmologically salt thereof; phosphotine iodide; demecarium bromide; cyclopentolate; homatropine; scopolamine; chlortetracycline; bacitracin; neomycin; polymixin; gramicidin; oxytetracycline; chloramphenicol; gentamycin; penicillin; erythromycin; carbachol; sulfacetamide; polymixin B′, idoxuridine; isoflorophate; fluoromethalone; dexamethasone; hydrocortisone; hydrocortisone acetate; 21-phosphate; fluorocinolone; medrysone; prednisolone; methyl prednisolone; prednisolone 21-phosphate; prednisolone acetate; betamethasone; triamcinolone; enzymes; vitamins; minerals; 3-Hydroxykynurenine O-˜-DL-glucoside or a derivative thereof, citicholine; taurine; resveratrol, sodium jaluronate; or mixture thereof.
  • Preferred active ingredients are those which are not stable in water or in solution.
  • It is a further object of the present invention a method of preparation of the powder of the invention which comprises the following steps:
      • a) preparation of the gel dissolving in water the gelling agent, a buffer, a saccharide, and optionally one or more drugs useful for treating diseases of the eye;
      • b) the gel so obtained is divided in single doses and put into vials;
      • c) to obtain a powder the vials of step b) are lyophilized; alternatively the gel of point a) is directly subjected to Spray-drying procedure and the powder so obtained is put, in a suitable amount, into vials.
  • The powder so obtained before the use needs to be reconstituted with water or a solution.
  • It is a further object of the present invention a physiological supplement or medicament for ophthalmic use, which comprises the powder or the gel of the invention and one or more drugs useful for the treatment of diseases of the eyes; and optionally one or more excipients and/or regulators of the osmotic pressure ophthalmologically acceptable.
  • It is a further object of the present invention a physiological supplement or medicament for ophthalmic use, which comprises the powder or the gel of the invention and as a drug (as active ingredient) cysteamine.
  • It is a further object of the present invention a physiological supplement or medicament for ophthalmic use, which comprises the powder or the gel of the invention and the following components:
      • L-carnitine, or an ophthalmically acceptable salt thereof, 10 at a dose of 0.1-10%, a preferred dose is 1%;
      • taurine at a dose of 0.1-4%, a preferred dose is 0.5%;
      • sodium hyaluronate at a dose of 0.05-1.5%, a preferred dose is 0.2%;
      • vitamin E at a dose of 0.05-1.0%, a preferred dose is 0.2%;
      • manganese at a dose of 0.01-0.1 mg/L, a preferred dose is 0.051 mg/L;
      • zinc at a dose of 0.5-1.5 mg/L, a preferred dose is 1.02 mg/L;
      • sodium at dose of 5-5000 mg/L, a preferred dose is 30 mg/L;
      • potassium at a dose of 1-1000 mg/L, a preferred dose is 9 mg/L.
  • This physiological supplement or medicament is particularly useful for the treatment of dry eye syndrome.
  • It is a further object of the present invention a physiological supplement or medicament for ophthalmic use, which comprises the powder or the gel of the invention and the following components;
      • L-carnitine, or an ophthalmically acceptable salt thereof, at a dose of 5-15%; preferred dose is 10%;
  • taurine at a dose of 0.5-4%, a preferred dose is 2%;
  • sodium hyaluronate at a dose of 0.05-1.5%, a preferred dose is 0.2%;
  • vitamin E at a dose of 0.05-1.0%, a preferred dose is 0.2%;
      • manganese at a dose of 0.01-0.1 mg/L, a preferred dose is 0.051 mg/L;
      • zinc at a dose of 0.5-1.5 mg/L, a preferred dose is 1.02 mg/L;
      • sodium at dose of 5-5000 mg/L, a preferred dose is 30 mg/L;
  • potassium at a dose of 1-1000 mg/L, a preferred dose is 9 mg/L.
  • This physiological supplement or medicament is particularly useful for the treatment of corneal oedema.
  • It is a further object of the present invention a physiological supplement or medicament for ophthalmic use, which comprises the powder or the gel of the invention and the following components;
      • L-carnitine, or an ophthalmically acceptable salt thereof, at a dose of 1-10%, a preferred dose is 5%;
      • 3-Hydroxykynurenine O—3-DL-glucoside 0.01-1 mg/mL, a preferred dose is 0.1 mg/mL;
      • Taurine at a dose of 0.5-4%, a preferred dose is 2%;
      • Resveratrol at a dose of 0.05-3 mg/mL, a preferred dose is 0.3 mg/mL;
      • Sodium jaluronate at a dose of 0.05-1.5%, a preferred dose is 0.2%;
  • Vitamin E at a dose of 0.05-1%, a preferred dose is 0.2%;
  • zinc at a dose of 0.5-1.5 mg/L, a preferred dose is 1.02 mg/L;
  • manganese at a dose of 0.01-0.1 mg/L, a preferred dose is 0.051 mg/L;
  • sodium at a dose of 5-5000 mg/L, a preferred dose is 30 mg/L;
  • potassium at a dose of 1-1000 mg/L, a preferred dose is 9 mg/L.
  • It is a further object of the present invention a physiological supplement or medicament for ophthalmic use, which comprises
  • the powder or the gel of the invention and the following components:
      • acetyl L-carnitine, or an ophthalmically acceptable salt thereof, at a dose of 5-30%, a preferred dose is 20%;
      • 3-Hydroxykynurenine 0-3-DL-glucoside at a dose of 0.01-1 mg/mL, a preferred dose is 0.1 mg/mL;
      • Vitamin E at a dose of 0.1-5%, a preferred dose is 1%;
      • Vitamin A at a dose of 15000-35000 Ul, a preferred dose is 25000 UI.
  • This physiological supplement or medicament is particularly useful for the treatment of eye diseases due to ultraviolet radiation.
  • The physiological supplements or medicaments of the invention may further comprise one or more of the following active ingredients: antioxidants, vitamins, Borage oil;
      • epithelialising and anti-angiogenic agents; citicholine, humidifying agents; inorganic elements; regulator of the cellular osmolarity; antibiotics; antiviral and antifungal agents; L-carnitine and/or one or more alkanoyl L-carnitines selected from the group consisting of acetyl, propionyl, valeryl, isovaleryl, butyryl and isobutyryl L-carnitine, or a pharmaceutically acceptable salt thereof.
  • The powder or the gel of the invention, when combined with one or more ophthalmic drugs, is useful for preparing a medicament for the treatment of diseases of the eye.
  • Further object of the present invention is a kit comprising the powder of the invention in admixture with one or more active ingredients (useful in the ophthalmic field) and, separately, in the same or in a different container/vial, water or a liquid solution suitable for obtaining the gel of the invention.
  • Further object of the present invention is a kit comprising:
      • a) the powder of the invention (not mixed with a drug useful for ophthalmic use);
      • b) one or more active ingredient useful for ophthalmic use (in liquid, solid, cream, gel or powder form); and
      • c) water or a liquid solution suitable for obtaining the gel of the invention; in which the (three) ingredients are into the same container/vial in separate space, and said (three) components can be easily mixed together to obtain the gel of the invention which may be directly administered on the eye.
  • The expert in container for ophthalmic use can easily suggest suitable containers which contains, for example, the gel mixed with one or more drugs; or a powder and separately (in the same container) a liquid; or 2 different powders and a liquid; for single or multiple applications. Different containers/vials are also included in the present invention.
  • What is meant by pharmaceutically acceptable salt of L-carnitine or alkanoyl L-carnitine is any salt with an acid that does not give rise to toxic or side effects.
  • These acids are well known to pharmacologists and to experts in pharmacy. Non-limiting examples of such salts are: chloride, bromide, orotate, aspartate, acid aspartate, acid citrate, magnesium citrate, phosphate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulphate, acid sulphate, glucose phosphate, tartrate and acid tartrate, glycerophosphate, mucate, magnesium tartrate, 2-amino-ethanesulphonate, methanesulphonate, choline tartrate, trichloroacetate, and trifluoroacetate.
  • What is meant by pharmaceutically acceptable salt of L-carnitine or alkanoyl L-carnitine is also a salt approved by the FDA and listed in the publication Int. J. of Pharm. 33 (1986), 201-15 217, which is incorporated herein by way of a reference.
    • DISCUSSION OF THE DRAWINGS
  • FIG. 1 shows shear stress and viscosity vs shear rates of the gel prepared in EXAMPLE 1. The gel resisted the initial rotary motion and a sudden increase in shear stress was observed at higher shear rate. The gel began to flow after shear stress reached its yield point. This system is a Newtonian flow of the pseudoplastic type with no hysteresis.
  • FIG. 2 shows shear stress and viscosity vs shear rates of the gel prepared in EXAMPLE 2. The gel resisted the initial rotary motion and a sudden increase in shear stress was observed at higher shear rate. The gel began to flow after shear stress reached its yield point. This system is a Newtonian flow of the pseudoplastic type with no hysteresis.
  • FIG. 3 shows shear stress and viscosity vs shear rates of the gel prepared in EXAMPLE 3. It can be observed with this gel that shear stress increases linearly with an increase in shear rate. This gelatinous system presents typical non-Newtonian flow behavior.
  • FIG. 4 shows shear stress and viscosity vs shear rates of the gel prepared in EXAMPLE 4. The gel resisted the initial rotary motion and a sudden increase in shear stress was observed at higher shear rate. The gel began to flow after shear stress reached its yield point. This system is a Newtonian flow of the pseudoplastic type with no hysteresis.
  • FIG. 5 shows the cumulative amount of cysteamine released vs time profiles for gel prepared as in EXAMPLE 1. The drug released about 42% into the medium after 30 min and then in gradual fashion. Approximately 96% of the cysteamine was released from the gel after 6 h.
  • FIG. 6 shows the cumulative amount of cysteamine released vs time profiles for gel prepared as in EXAMPLE 2. The drug released about 46% into the medium after 30 min and then in gradual fashion. Approximately 98% of the cysteamine was released from the gel after 6 h.
    •
  • The following examples are illustrative, but not limiting the scope of the present invention. Reasonable variations, such as those occur to reasonable artisan, can be made herein without departing from the scope of the present invention.
  • Materials
  • Carbopol 974P NF (Noveon), cysteamine and all other chemicals, including tartaric acid and benzalconium chloride, were purchased from Sigma and were used as received.
    • EXAMPLE 1
  • 3 g of Carbopol 974P NF (Noveon) were slowly added to 190 mL of water containing 20 mg of benzal conium chloride, the solution was kept under stirring at room temperature for 18 h. Then, 500 mg of L-tartaric acid, followed by 6 g of mannitol and finally 1 g of cysteamine were added, keeping the solution under stirring until the cysteamine was completely solubilized.
  • The gelatinous system thus obtained was divided into fractions of 3 mL in 10-mL vials. Said vials were lyophilized for 24 h and a white solid was obtained.
  • Adding 3 mL of water to the lyophilized vial a gelatinous system having the following characteristics was readily obtained:
      • pH=4.0-4.3;
      • Osmotic pressure=229 mOsm/kg.
    EXAMPLE 2
  • 10 mg of benzalconium chloride and 500 mg of L-tartaric acid were added to 95 g of a 1.5% Carbopol 974P NF aqueous solution. A very fluid opalescent solution was obtained. To the opalescent solution were added 3 g of sorbitol and 1 g of cysteamine. The mixture so obtained was kept under stirring until the cysteamine was completely solubilized.
  • The gelatinous system thus obtained was divided into fractions of 3 mL in 10-mL vials. Said vials were lyophilized for 24 h and a white solid was obtained.
  • Adding 3 mL of water to the lyophilized vial a gelatinous system having the following characteristics was readily obtained:
      • Osmotic pressure=267 mOsm/kg;
      • pH=4.5-5.0.
    EXAMPLE 3
  • 1 g of L-tartaric acid was added to 95 g of a 1.5% Carbopol 974P NF aqueous solution, a very fluid opalescent solution was obtained. To this solution 3 g of sorbitol and 1 g of cysteamine were added, the mixture so obtained was kept under stirring until the cysteamine was completely solubilized.
  • The gelatinous system thus obtained was divided into fractions of 3 mL in 10-mL vials. Said vials were lyophilized for 24 h and a white solid was obtained.
  • Adding 3 mL of water to the lyophilized vial a gelatinous system having the following characteristics was readily obtained:
      • pH=4.0-4.3
      • Osmotic pressure=297 mOsm/kg.
    EXAMPLE 4
  • In 400 mL of water 3 g of Carbopol 974P NF, 2 g of tartaric 25 acid, 6 g of lactose and finally 2 g of cysteamine in the sequence above reported, at room temperature, were dissolved. The slightly viscous solution, constantly kept under stirring was concentrated through a Spray-drying (Buchi B-191) under the following conditions: Inlet=60° C., ASP=82, Pump=0.06.
  • A white solid was obtained.
  • Adding 200 mL of water, to the white solid, a gelatinous system having the following characteristics was readily obtained:
      • pH=4.0-4.3
      • Osmotic pressure=225 mOsm/kg.
  • Reological Studies
  • The reo logical studies were carried out with a rotational viscometer of the concentric cylinder type (Viscometer TV-10 Toky Sangyo equipped with a small sample adapter and rotor type M3). The viscosity and shear stress of the samples were measured at various rates at 25° C. The temperature was maintained within +/0.1° C. by a recirculating bath connected to the viscometer. The samples were equilibrated for five minutes to reach the running temperature prior to each measurement.
  • In Vitro Release Studies
  • In vitro release experiments were carried out with a dissolution instrument (Sotax AT 7 smart) equipped with a cell cream. Approximately 2 g of gel containing cysteamine prepared as reported in EXAMPLES 1 and 2 were weighed in the cell cream and placed in a 1000-mL vessel containing 500 mL of 50 mM acetate buffer, 25 pH=4.5. The experiments were carried out at 37° C. and with a 50 rpm stirring paddle. At regular intervals, 1 mL of solution was withdrawn from the vessel and filtered using a 0.2 micron filter (Millez-FG Millipore) analyzed by HPLC to determine cysteamine concentration.
  • The HPLC chromatographic system composed of a pump (Waters 600); and autosampler (Waters 717); a UV detector (Waters 486) and integrator (Waters Empower 2). An inverse phase silica column (ODS-3 4.6×250 mm 5 micron) was used for the drug separation, pH=3, and as mobile phase was used a sodium dihydrogen phosphate buffer system. The flow rate and UV wavelength were 0.8 mL/min and 205 nm, respectively. The drug concentrations were determined by measuring the peak area in comparison with the peak area of known standards.
  • Carbopol® is a registered trademark of Noveon, Inc. (formerly B.F. Goodrich Co.) for a family of polymers that are used as thickeners, suspending agents and stabilizers.
  • L-carnitine and its alkanoyl derivatives are known compounds, the reparation process for which is described in U.S. Pat. No. 4,254,053.
  • 3-Hydroxykynurenine 0-3-DL-glucoside is a product sold by Sigma-Aldrich, catalogue 2006; product code n° H 1771.
  • The physiological supplement or medicament according to the present invention may be bought with or without medical prescription.
  • The physiological supplements or medicaments according to the present invention are composed of active ingredients which are familiar to operators in the medical field and already in use in clinical practice, and their pharmacotoxicological profiles are known.
  • Their procurement therefore is very easy, inasmuch as these are products which have been on the market now for a long time and are of a grade suitable for human or animal administration.
  • In the following are reported non limiting examples of composition according to the present invention.
  • Formulation 1
  • The powder or the gel of the invention and cysteamine. This physiological supplement or medicament is particularly useful for the treatment of cystinosis.
  • Formulation 2
  • The powder or the gel of the invention and the following components (active ingredients):
      • L-carnitine 1%;
      • Taurine 0.5%;
      • sodium hyaluronate 0.2%;
      • vitamin E 0.2%;
      • manganese 0.051 mg/L;
      • zinc 1.02 mg/L;
      • sodium 30 mg/L;
      • potassium 9 mg/L;
      • Osmolality of about 125 mOsmols/kg.
  • This physiological supplement or medicament is particularly useful for the treatment of dry eye syndrome.
  • Formulation 3
  • The powder or the gel of the invention and the following components:
      • L-carnitine 10%
      • taurine 2%
      • sodium jaluronate 0.2%
      • vitamin E 0.2%
      • zinc 1.02 mg/L
      • manganese 0.051 mg/L
      • sodium 30 mg/L
      • potassium 9 mg/L
      • Osmolality of about 1200 mOsmols/kg.
  • This physiological supplement or medicament is particularly useful for the treatment of corneal oedema.
  • Formulation 4
  • The powder or the gel of the invention and the following components:
      • L-carnitine 5%
      • 3-HydroXYkYnurenine O-P-DL-glucoside 0.1 mg/mL
      • Taurine 2%
      • Resveratrol 0.3 mg/mL
      • Sodium jaluronate 0.2%
      • Vitamin E 0.2%
      • Zinc 1.02 mg/L
      • Manganese 0.051 mg/L
      • sodium 30 mg/L
      • 5 potassium 9 mg/L.
  • This physiological supplement or medicament is particularly useful for the treatment of eye diseases due to ultraviolet radiation.
  • Formulation 5
  • The powder or the gel of the invention and the following components:
      • Acetyl L-carnitine 20%
      • 3-Hydroxykynurenine O-β-DL-glucoside 0.1 mg/ml
      • Vitamin E 1%
      • Vitamin A 25000 UI.
  • This physiological supplement or medicament is particularly useful for the treatment of eye diseases due to ultraviolet radiation.

Claims (13)

1. A solid powder comprising:
a carboxy vinyl polymer;
a buffer;
a saccharide; and
L-carnitine and/or one or more alkanoyl L-carnitine,
said solid powder providing a gel suitable for ophthalmic use when reconstituted in water.
2. The solid powder of claim 1, wherein the carboxy vinyl polymer is carbopol.
3. The solid powder of claim 1, wherein the buffer is a hydroxyacid or a dicarboxylic acid selected from the group consisting of phosphate, boric acetate, citrate, lactate, tartrate, maleate, succinate and fumarate buffer.
4. The solid powder of claim 1, wherein the saccharide is selected from the group consisting of glucose, fructose, mannitol, sorbitol, lactose, trehalose and maltose.
5. The solid powder of claim 1, further comprising an excipient, a diluent or a regulator of the osmotic pressure ophthalmologically acceptable.
6. Physiological supplement comprising the solid powder of claim 1 and further comprising:
L-carnitine    1%; taurine  0.5%; sodium hyaluronate  0.2%; vitamin E  0.2%; manganese 0.051%; zinc  1.02%; sodium 30 mg/L; potassium  9 mg/L.
7. Physiological supplement comprising the solid powder of claim 1 and further comprising:
L-carnitine  10%; taurine   2%; sodium hyaluronate 0.2%; vitamin E 0.2%; zinc  1.02 mg/L; manganese 0.051 mg/L; sodium   30 mg/L; potassium    9 mg/L.
8. Physiological supplement comprising the solid powder of claim 1 and further comprising:
L-carnitine   5%; 3-Hydroxykynurenine O-P-DL-glucoside  0.1 mg/mL; taurine   2%; resveratrol  0.3 mg/mL; sodium jaluronate 0.2%; vitamin E 0.2%; zinc  1.02 mg/L; manganese 0.051 mg/L; sodium   30 mg/L; potassium    9 mg/L.
9. Physiological supplement comprising the solid powder of claim 1 and further comprising:
acetyl L-carnitine 20%; 3-Hydroxykynurenine O-β-DL-glucoside 0.1 mg/mL; vitamin E  1%; vitamin A 25000 UI.
10. Kit comprising the solid powder of claim 1 and water or a liquid solution.
11. Kit of claim 10, in which each component is packaged in the same vial or in two different vials.
12. Kit comprising:
a) the powder of claim 1, without L-carnitine and/or one or more alkanoyl L-carnitine;
b) L-carnitine and/or one or more alkanoyl L-carnitine in the form of liquid, solid, cream, gel or powder; and
c) water or a liquid solution.
13. Kit of claim 12, wherein each component is packaged in a separate form in the same vial or in different vials.
US13/749,790 2006-12-22 2013-01-25 Gel useful for the delivery of ophthalmic drugs Abandoned US20130137651A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/749,790 US20130137651A1 (en) 2006-12-22 2013-01-25 Gel useful for the delivery of ophthalmic drugs

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP06126981.7 2006-12-22
EP06126981 2006-12-22
PCT/EP2007/062929 WO2008077712A1 (en) 2006-12-22 2007-11-28 Gel useful for the delivery of ophthalmic drugs
US51744509A 2009-06-16 2009-06-16
US13/749,790 US20130137651A1 (en) 2006-12-22 2013-01-25 Gel useful for the delivery of ophthalmic drugs

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2007/062929 Division WO2008077712A1 (en) 2006-12-22 2007-11-28 Gel useful for the delivery of ophthalmic drugs
US51744509A Division 2006-12-22 2009-06-16

Publications (1)

Publication Number Publication Date
US20130137651A1 true US20130137651A1 (en) 2013-05-30

Family

ID=38050259

Family Applications (2)

Application Number Title Priority Date Filing Date
US12/517,445 Expired - Fee Related US8389014B2 (en) 2006-12-22 2007-11-28 Gel useful for the delivery of ophthalmic drugs
US13/749,790 Abandoned US20130137651A1 (en) 2006-12-22 2013-01-25 Gel useful for the delivery of ophthalmic drugs

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US12/517,445 Expired - Fee Related US8389014B2 (en) 2006-12-22 2007-11-28 Gel useful for the delivery of ophthalmic drugs

Country Status (12)

Country Link
US (2) US8389014B2 (en)
EP (1) EP2094236A1 (en)
JP (1) JP5315252B2 (en)
KR (1) KR101433152B1 (en)
CN (1) CN101534794A (en)
AU (1) AU2007338210B2 (en)
BR (1) BRPI0720434A2 (en)
CA (1) CA2667072C (en)
EA (1) EA016795B1 (en)
MX (1) MX2009005644A (en)
SG (1) SG176525A1 (en)
WO (1) WO2008077712A1 (en)

Families Citing this family (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA98449C2 (en) 2005-12-13 2012-05-25 Инсайт Корпорейшин Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors
DK2173752T4 (en) 2007-06-13 2022-08-01 Incyte Holdings Corp Salte af janus-kinase-inhibitor (r)-3-(4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropannitril
TWI474817B (en) * 2008-07-04 2015-03-01 Sigma Tau Ind Farmaceuti Compounds useful for the prevention or treatment of accommodative asthenopia
ITMI20081947A1 (en) * 2008-11-05 2010-05-06 Vitrupharma Srl NEW USE OF A RESVERATROL COMBINATION OR ITS ANALOGUE AND A METABOLITY OF CISTEIN
NZ596374A (en) 2009-05-22 2014-01-31 Incyte Corp 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl]octane- or heptane-nitrile as jak inhibitors
SG176130A1 (en) 2009-05-22 2011-12-29 Incyte Corp N-(HETERO)ARYL-PYRROLIDINE DERIVATIVES OF PYRAZOL-4-YL-PYRROLO[2,3-d]PYRIMIDINES AND PYRROL-3-YL-PYRROLO[2,3-d]PYRIMIDINES AS JANUS KINASE INHIBITORS
TW201113285A (en) 2009-09-01 2011-04-16 Incyte Corp Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
EP2363126A1 (en) * 2010-03-04 2011-09-07 SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A. Composition comprising as active ingredient L-carnitine in combination with hydroxykynurenine-O-beta-DL-glucoside, for the prevention and/or treatment of pathologies of the eye due to ultraviolet radiation
PL3354652T3 (en) 2010-03-10 2020-11-16 Incyte Holdings Corporation Piperidin-4-yl azetidine derivatives as jak1 inhibitors
SG185567A1 (en) 2010-05-21 2012-12-28 Incyte Corp Topical formulation for a jak inhibitor
WO2012068450A1 (en) 2010-11-19 2012-05-24 Incyte Corporation Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors
WO2012068440A1 (en) 2010-11-19 2012-05-24 Incyte Corporation Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as jak inhibitors
CN102614127B (en) * 2011-01-28 2014-07-30 北京万生药业有限责任公司 Resveratrol nanoscale dispersoid and preparation method thereof
US8691807B2 (en) 2011-06-20 2014-04-08 Incyte Corporation Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors
TW201313721A (en) 2011-08-18 2013-04-01 Incyte Corp Cyclohexyl azetidine derivatives as JAK inhibitors
UA111854C2 (en) 2011-09-07 2016-06-24 Інсайт Холдінгс Корпорейшн METHODS AND INTERMEDIATE COMPOUNDS FOR JAK INHIBITORS
CN102579320B (en) * 2012-02-29 2013-07-10 四川梓橦宫药业有限公司 Citicoline sodium brain-targeting thermosensitive gel and preparation method thereof
TW201406761A (en) 2012-05-18 2014-02-16 Incyte Corp Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors
JP6275137B2 (en) * 2012-08-06 2018-02-07 ベイラー カレッジ オブ メディスンＢａｙｌｏｒ Ｃｏｌｌｅｇｅ Ｏｆ Ｍｅｄｉｃｉｎｅ Therapeutic drug dispensing device and method for making the same
PE20200175A1 (en) 2012-11-15 2020-01-24 Incyte Holdings Corp SUSTAINED RELEASE RUXOLITINIB DOSAGE FORMS
JP2016501931A (en) 2012-11-21 2016-01-21 ユニバーシティー オブ ルイヴィル リサーチ ファウンデーション，インコーポレーテッドＵｎｉｖｅｒｓｉｔｙ Ｏｆ Ｌｏｕｉｓｖｉｌｌｅ Ｒｅｓｅａｒｃｈ Ｆｏｕｎｄａｔｉｏｎ，Ｉｎｃ． Compositions and methods for reducing oxidative damage
PT3489239T (en) 2013-03-06 2021-12-17 Incyte Holdings Corp Processes and intermediates for making a jak inhibitor
EP2783695A1 (en) * 2013-03-28 2014-10-01 SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A. Physiological supplement or medicament for ophthalmic use containing L-carnitine or alkanoyl L-carnitines in combination with eledoisin
TWI659209B (en) * 2013-06-17 2019-05-11 地平線罕見醫學製藥有限責任公司 Methods for analyzing cysteamine compositions
TWI789516B (en) 2013-08-07 2023-01-11 美商英塞特公司 Sustained release dosage forms for a jak1 inhibitor
US9791359B2 (en) * 2013-12-06 2017-10-17 Instituto Mexican Del Petroleo Process for determining the incompatibility of mixtures containing heavy and light crudes
FR3018045B1 (en) * 2014-02-28 2017-06-16 Thea Lab REMANENT OPHTHALMIC COMPOSITION, IN PARTICULAR FOR THE TREATMENT OF EYE DROUGHT
US9498467B2 (en) 2014-05-30 2016-11-22 Incyte Corporation Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1
EP3256136A4 (en) 2015-02-09 2018-11-21 University Of Louisville Research Foundation, Inc. Ophthalmic compositions and methods for reducing oxidative damage to an eye lens
CN105125491A (en) * 2015-10-19 2015-12-09 滨州医学院烟台附属医院 Resveratrol micelle eye drops and preparation method thereof
EP3365022A4 (en) * 2015-10-25 2019-07-24 IVIEW Therapeutics, Inc. Pharmaceutical formulations that form gel in situ
GB201609940D0 (en) 2016-06-07 2016-07-20 Novabiotics Ltd Microparticles
US10905660B2 (en) * 2016-06-07 2021-02-02 Novabiotics Limited Microparticles
WO2018140594A1 (en) 2017-01-25 2018-08-02 Adare Pharmaceuticals, Inc. Cysteamine prodrugs
EP3412276A3 (en) * 2017-06-09 2019-07-17 Omnivision GmbH Composition for the treatment of dry eye
WO2019113487A1 (en) 2017-12-08 2019-06-13 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
RU2688687C1 (en) * 2017-12-26 2019-05-22 Илья Александрович Марков Eye gel drops for treatment of inflammatory, virus, bacterial, allergic, metabolic, traumatic diseases
SG11202007164UA (en) 2018-01-30 2020-08-28 Incyte Corp Processes for preparing (1 -(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidine-4-one)
SI3773593T1 (en) 2018-03-30 2024-08-30 Incyte Corporation TREATMENT OF HIDRADENITIS SUPPURATIVE WITH JAK INHIBITORS
CN109528628B (en) * 2018-12-14 2022-02-08 北京中医药大学 Medicinal composition containing levocarnitine and preparation method and application thereof
WO2021156856A1 (en) * 2020-02-03 2021-08-12 Resdevco Research And Development Co. Ltd. Topical opthalmological composition containing hyaluronate and taurine having non-newtonian rheological properties
CN111202746B (en) * 2020-02-27 2021-03-16 潍坊医学院附属医院 Compound preparation for eyes and preparation method thereof
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
RU2745124C1 (en) * 2020-07-02 2021-03-22 Общество с ограниченной ответственностью "МедикалСайнс" Bioactive composition based on a crosslinked hyaluronic acid salt containing resveratrol and a method of its preparation
EP4419204A4 (en) * 2021-10-18 2025-03-12 Vsy Biyoteknoloji Ve Ilac Sanayi Anonim Sirketi OPHTHALMIC FORMULATION FOR THE TREATMENT AND PREVENTION OF CATARACTS AND MANUFACTURING METHOD THEREFOR
EP4218717A1 (en) * 2022-02-01 2023-08-02 Laboratoires THEA Ophthalmic composition comprising resveratrol for treating dry eye syndrome

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050092969A1 (en) * 2003-10-08 2005-05-05 Kaneka Corporation Method of stabilizing compound having quinone skeleton and stabilized composition
WO2007003481A1 (en) * 2005-07-01 2007-01-11 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of l-carnitine or of alkanoyl l-carnitines for the preparation of a physiological supplement or medicament for ophthalmic use in the form of eye-drops
US8158679B2 (en) * 2006-12-11 2012-04-17 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of L-carnitine for the preparation of a medicament in the form of eye-drops for treating corneal diseases

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8701258D0 (en) * 1987-03-26 1987-03-26 Pharmacia Ab A COMPOSITION FOR THE TOPICAL TREATMENT OF GLAUCOMA OR OCULAR HYPERTENSION
FR2679135B1 (en) 1991-07-18 1995-05-19 Europhta Sa Laboratoire NOVEL OPHTHALMIC COMPOSITIONS WITH IMPROVED ADHESIVITY AND METHODS OF PREPARING THE SAME.
JP2873530B2 (en) 1991-12-13 1999-03-24 参天製薬株式会社 Carboxyvinyl polymer-containing ophthalmic base showing Newtonian viscosity
US6258847B1 (en) * 1996-09-25 2001-07-10 Samir Chachoua Use of 2-mercaptoethanolamine (2-MEA) and related aminothiol compounds and copper(II)-3,5 di-isopropyl salicylates and related compounds in the prevention and treatment of various diseases
BR9913955A (en) * 1998-09-25 2001-06-12 Alcon Lab Inc Comfortable and sustained-release ophthalmic composition and method for eye therapy
ES2228128T3 (en) * 1998-11-13 2005-04-01 Continental Projects Limited HIALURONIC ACID COMPLEX / CARNITINE AND PHARMACEUTICAL AND COSMETIC COMPOSITIONS.
EP1183027A4 (en) * 1999-06-16 2003-02-05 Nastech Pharmaceutical Co PHARMACEUTICAL FORMULATIONS AND METHODS COMPRISING INTRA-NASAL DELIVERY MORPHINE
PE20020146A1 (en) * 2000-07-13 2002-03-31 Upjohn Co OPHTHALMIC FORMULATION INCLUDING A CYCLOOXYGENASE-2 (COX-2) INHIBITOR
FR2832311B1 (en) * 2001-11-21 2004-04-16 Besins Int Belgique FILM-FORMING POWDER, COMPOSITIONS COMPRISING SAME, PREPARATION METHODS AND USES THEREOF
CN101327325A (en) * 2002-07-30 2008-12-24 奥默罗斯公司 Ophthalmologic irrigation solutions and method
US6803046B2 (en) * 2002-08-16 2004-10-12 Bracco International B.V. Sincalide formulations
JP2005008596A (en) * 2003-06-20 2005-01-13 Kobayashi Pharmaceut Co Ltd Ophthalmological composition
AU2005267028A1 (en) * 2004-07-22 2006-02-02 Genentech, Inc. Method of treating Sjogren's syndrome

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050092969A1 (en) * 2003-10-08 2005-05-05 Kaneka Corporation Method of stabilizing compound having quinone skeleton and stabilized composition
WO2007003481A1 (en) * 2005-07-01 2007-01-11 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of l-carnitine or of alkanoyl l-carnitines for the preparation of a physiological supplement or medicament for ophthalmic use in the form of eye-drops
US7655698B2 (en) * 2005-07-01 2010-02-02 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of L-carnitine or of alkanoyl L-carnitines for the preparation of a physiological supplement or medicament for opthalmic use in the form of eye drops
US8377988B2 (en) * 2005-07-01 2013-02-19 Sigma-Tau Industrie Farmaceutiche Riunite Spa Use of L-carnitine or of alkanoyl L-carnitines for the preparation of a physiological supplement or medicament for ophthalmic use in the form of eye drops
US8158679B2 (en) * 2006-12-11 2012-04-17 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of L-carnitine for the preparation of a medicament in the form of eye-drops for treating corneal diseases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Gülçin, Antioxidant and antiradical activities of L-carnitine, Life Sci. 2006 Jan 18;78(8):803-11. Epub 2005 Oct 25, printed from http://www.ncbi.nlm.nih.gov/pubmed/16253281, 1 page, Abstract only *
Winfield, Pharmaceutical Practice, Ophthalmic Products-pH adjustment, Churchill Livingstone, 2004, 264-273 *

Also Published As

Publication number Publication date
SG176525A1 (en) 2011-12-29
AU2007338210B2 (en) 2013-01-31
US8389014B2 (en) 2013-03-05
KR101433152B1 (en) 2014-08-22
KR20090091769A (en) 2009-08-28
CN101534794A (en) 2009-09-16
WO2008077712A1 (en) 2008-07-03
EA200970623A1 (en) 2009-10-30
EA016795B1 (en) 2012-07-30
JP2010513366A (en) 2010-04-30
EP2094236A1 (en) 2009-09-02
CA2667072C (en) 2015-11-24
CA2667072A1 (en) 2008-07-03
JP5315252B2 (en) 2013-10-16
MX2009005644A (en) 2009-06-08
US20100069482A1 (en) 2010-03-18
AU2007338210A1 (en) 2008-07-03
BRPI0720434A2 (en) 2014-01-07

Similar Documents

Publication Publication Date Title
US8389014B2 (en) Gel useful for the delivery of ophthalmic drugs
US10213392B2 (en) Pharmaceutical composition for use in medical and veterinary ophthalmology
EP3463360B1 (en) Atropine-containing aqueous composition
EP3954362A1 (en) Method of increasing bioavailability and/or prolonging ophthalmic action of a drug
EA034839B1 (en) Ophthalmic solution
EP2002841A1 (en) Ophthalmic composition comprising xanthan gum and glucose
EP2219630A2 (en) Compositions for the treatment and prevention of eyelid swelling comprising an osmotically active ingredient and a vasoconstrictor
AU785285B2 (en) Methods and compositions for treating and preventing posterior segment ophthalmic disorders
WO2017066052A1 (en) Formulations and methods for treating high intraocular pressure
JPS61143318A (en) Novel drug and preparation
CN115487139B (en) Puerarin gellan gum ionic in-situ gel eye drops and preparation method
EP2758031A1 (en) Ophthalmic gel compositions
EP4167965B1 (en) Use of high molecular weight hyaluronic acid as ocular transporting vehicle
KR20230145458A (en) Aqueous pharmaceutical composition containing ursodeoxycholic acid or its salt
US20120028947A1 (en) Ophthalmic Compositions
EP4454639A1 (en) Ophthalmic composition comprising carbomer and taurine
EP4312976B1 (en) Water-soluble topical ophthalmic preparation containing lutein and production method thereof
TWI805705B (en) Methods of use and pharmaceutical compositions of a selective syk inhibitor

Legal Events

Date Code Title Description
AS Assignment

Owner name: SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P.A.,

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LONGO, ANTONIO;SANTANIELLO, MOSE;PESCOSOLIDO, NICOLA;AND OTHERS;REEL/FRAME:029691/0787

Effective date: 20090511

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载