Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
  • A61K38/44—Oxidoreductases (1)
  • A61K38/446—Superoxide dismutase (1.15)
• • 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
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/04—Artificial tears; Irrigation 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
  • A61P27/14—Decongestants or antiallergics

Definitions

• the invention relates to the use of an antioxidant chosen from group 5 consisting of superoxide dismutases (SODs), superoxide dismutase mimetics, derivatives of superoxide dismutases, racemic alpha lipoic acid, enantiomers of alpha lipoic acid and mixtures of these antioxidants, for the manufacture of a medicament intended for the treatment and / or prevention of ocular surface conditions, in humans or
• the ocular surface is the transition mucosa between the deep ocular medium and the external medium. It is necessary to maintain the integrity of the cornea, transparent eye window open to the outside for the transmission of images to the retina, the loss of its transparency being synonymous with blindness,
• the ocular surface As an anatomical and functional barrier, protecting the eye from external aggressors. It is formed by a triad, the cornea, the tear film and the conjunctiva (Hoang-Xuant T 1998, Pouliquen Y. 1991, Rigal D., 1993, Baudouin Ch. 1998).
• the corneal epithelium provides a barrier function necessary for the protection of the underlying corneal constituents and of the endocular environment.
• the tear film consists of three layers: a lipid layer 0.1 ⁇ m thick, an aqueous intermediate layer 7 ⁇ m and a layer
• mucus secreted by the goblet cells present in the conjunctival epithelium spreads over the ocular surface. It is related to the apical cytoplasmic membrane of the surface cells via the glycocalyx.
• the tear film acts by physico-chemical properties
• Tears actively participate in the non-specific defense mechanisms of the cornea thanks to the presence of lactoferrin, lysosyme and immunoglobulins. To these non-specific means brought by tears are added the specific elements of the conjunctival tissue.
• the lacrimal mucus, glycolipids and glycoproteins complex of the epithelial plasma membranes conditions the quality of the coma surface.
• the epithelial surface is hydrophobic and the aqueous phase of the tears, instead of spreading, is deposited in drops.
• the mucin by decreasing the surface tension allows the aqueous component of the tears to spread and be adsorbed by the epithelial surface, thus maintaining a stable tear film between each blink.
• any abnormality in the mucus layer will compromise the stability of the tear film and cause it to rupture to form dry spots and this very quickly after the effect of blinking resurfacing.
• Apical expansions, such as microvilli, microplates of surface cells by increasing the adhesion of the tear film thus contribute to better stability of the tear film.
• the alteration of this como-conjunctival surface promotes bacterial adhesion to the epithelial surfaces.
• the cornea also has the conjunctiva.
• the conjunctiva is a vascularized mucous membrane that covers the surface of the globe and the posterior surface of the upper and lower eyelids. It is responsible for the secretion of mucus essential for the stability of the tear film and the Comean transparency.
• Oxidative stress plays a major role through oxygenated free radicals, species highly toxic to the mucous membranes, due to their high content of polyunsaturated fatty acids.
• Free radicals are chemical species having on their peripheral orbital an electron not coupled, celibate, giving them a great instability compared to the presence of two electrons in periphery (Pryor ' WA.
• the primary radicals are the superoxide anion (0 2 .-), the starting point of the radical chains starting from molecular oxygen.
• the superoxide anion (0 2 .-) releases hydrogen peroxide (H 2 0 2 ) into the medium.
• H 2 0 2 is then converted into a hydroxyl radical (OH.), A very reactive species.
• Nitric oxide Is a simple molecule and a free radical centered on the nitrogen atom. It is formed in vivo by the constitutive NO synthases (NOS) but under certain pathological conditions, another NOS can be expressed, it is the inducible NOS.
• N0 2 and N 2 0 3 are qualified as reactive nitrogen species, responsible for nitrosative stress.
• the superoxide anion (0 2 .-) can react with nitrogen monoxide (NO.)
• NO. nitrogen monoxide
• ONOO- peroxynitrite anion
• Secondary radicals come from the membrane lipid peroxidation of polyunsaturated fatty acids (arachidonic acid for example) which are the most sensitive targets.
• This lipid peroxidation is a chain reaction initiated by the hydroxyl radical (OH.) With the carbon chain of a polyunsaturated fatty acid (L) thus forming an alkyl radical (L.).
• O 2 molecular oxygen
• the alkyl radicals (L.) lead to the release of peroxyl (ROO.) And alkoxyl (RO.) Radicals, during propagation reactions.
• ROO. peroxyl
• RO. alkoxyl Radicals
• Oxidative attacks are directed on the side groups or on the asymmetric carbon of the amino acids.
• carbonyl groups by the direct oxidation of amino acids is considered to be one of the major oxidative modifications of proteins. These carbonyl groups are used as markers for the oxidation of proteins (Dean RT et al. 1997).
• the bases of DNA are very sensitive to the action of biological oxidants.
• the superoxide anion (0 2 .-) can oxidize DNA through the formation of the hydroxyl radical (OH.) In the presence of iron (Henle ES and Linn S. 1997).
• OH. hydroxyl radical
• iron iron
• Free radicals thus have deleterious effects on the cells of the cornea and conjunctiva, ranging from the presence of erosions to severe ulcers, very disabling.
• Environmental factors are permanent sources of attack on the ocular surface.
• Blepharitis and ocular rosacea are also frequent causes of qualitative dry eye, with infectious and inflammatory components. These conditions lead to a dysfunction of the Meibonian glands which disturbs the composition of the lipid phase of the tear film and increases the rate of evaporation of tears. These phenomena manifest themselves clinically by a shortening of the GOAL (resistance to the stretching of tears and lead to epithelial hyperosmolarity. These meibomian dysfunctions, result in cellular suffering, rupture of the intercellular junctions, loss of goblet cells and probably a deficit secretion of mucus by conjunctival cells (Toda I. et al. 1995).
• a common dryness is observed by degenerative atrophy of the lacrimal glands, treated with eye drops, unable to relieve patients. Where irritant eye drops accumulate, particularly in the area of lower palpebral or nasal cleft, a toxic effect may be observed.
• preservatives such as benzalkonium chloride, quaternary ammoniums. These preservatives also have a significant degree of toxicity through the production of free radicals. This results in reduced resistance to tear stretching, direct toxicity to epithelial cells, with epithelial erosions and an inflammatory reaction. It should be noted that the half-life of benzalkonium is 20 hours and that significant levels of preservatives persist 168 hours after instillation of a single drop (De Saint Jean et al. 1999).
• the inflammatory reaction is an essential component of dry eye syndromes. It is therefore necessary to develop treatments adapted to dry eye syndrome and much more generally to affections of the ocular surface.
• topical products containing preservatives (antiseptic substances) on the surface of the eye can modify the balance of the ocular surface and be at the origin of serious anomalies of the conjunctiva and the cornea which can develop at low noise and only appear very late, sometimes in completely unexpected ways.
• BAC Benzalkonium chloride
• racemic alpha-lipoic acid or its R + / R " enantiomers is an antioxidant which has been used in particular for protection against UV rays, peripheral neuropathies, certain lipodistrophies, and for slowing the replication of HIV.
• compositions for oral administration for its protective effects in the retina, in age-related degeneration, glaucoma and increased pressure.
• ocular that is to say for affections not of the ocular surface but of the posterior segment of the eye.
• SODs superoxide dismutases
• Cu / Zn SODs are used in cosmetics and for the treatment of cancers, in which case they are administered intravenously.
• the object of the invention is to enable not only a basic treatment of the affections of the ocular surface which can cause dryness of the eye but also the prevention of these affections.
• the invention provides the use of an antioxidant chosen from the group consisting of superoxide dismutases (SODs), mimetics, superoxide dismutases, derivatives of superoxide dismutases, racemic alpha lipoic acid, l enantiomeres R + of alpha-lipoic acid, enantiomer R " of alpha-lipoic acid and mixtures of these compounds, for the manufacture of a medicament intended for the treatment and / or prevention of ocular affections surface in humans or animals.
• SODs superoxide dismutases
• mimetics superoxide dismutases
• derivatives of superoxide dismutases derivatives of superoxide dismutases
• racemic alpha lipoic acid l enantiomeres R + of alpha-lipoic acid
• enantiomer R " of alpha-lipoic acid and mixtures of these compounds
• the antioxidant is an SOD and / or a derivative and / or a mimetic thereof.
• the SOD is a wheat SOD.
• SOD is present in the drug at a concentration between 1 jug / ml and 500 jug / mJ, preferably between 25 ⁇ g / ml and 50 ⁇ g / ml.
• the antioxidant is racemic alpha-lipoic acid and / or one of its R + , R ⁇ enantiomers
• racemic alpha lipoic acid it is preferred, however, in this embodiment, to use racemic alpha lipoic acid.
• the racemic alpha-lipoic acid or one of its R + , R " enantiomers is present in the drug at a concentration of between 0.05 ⁇ g / ml and per 200 ⁇ g / ml, preferably between 0.5 ⁇ g / ml and 5 ⁇ g / ml.
• the antioxidant is a mixture of racemic alpha-lipoic acid, and / or one of its R + , R " enantiomers, and one or more SODs, and / or a derivative and / or mimetic thereof.
• alpha-lipoic acid, and / or its R + , R " enantiomers is present in the drug in a concentration of 0.05 ⁇ g / ml to 200 ⁇ g / ml, preferably of 0.5 ⁇ g / ml to 5 ⁇ g / ml and the SOD, and / or its derivative and / or its mimetic, is present in the drug at a concentration of between 1 ⁇ g / ml and 500 ⁇ g / ml, preferably between 25 ⁇ g / ml and 50 ⁇ g / ml.
• the ocular surface conditions treated are those which cause dryness of the eye.
• the surface eye conditions treated can be an alteration of corneal cells.
• the treated eye conditions can be due to exposure to environmental agents such as ozone, nitrogen oxide, sulfur dioxide, volatile organic compounds and particles released by diesel engines. They may also have been caused by prolonged exposure to a computer screen, television screen or video monitor.
• environmental agents such as ozone, nitrogen oxide, sulfur dioxide, volatile organic compounds and particles released by diesel engines. They may also have been caused by prolonged exposure to a computer screen, television screen or video monitor.
• the surface eye conditions treated are those due to the wearing of lenses.
• the eye conditions treated are those due to exposure to salt water and / or chlorinated water.
• These eye conditions can also be due to exposure to ultraviolet A and / or B and / or C, X-rays.
• the treated eye conditions can also be due to exposure to bacteria, viruses and / or fungi.
• Gougerot-Sjôgren syndrome, blepharitis and ocular rosacea can also be treated.
• eye conditions due to exposure to a preservative (s), present (s) in compositions administered to the eye by the topical route are not only treated but also, can be prevented thanks to the invention, and more particularly when the preservative is benzalkonium chloride.
• the medicament produced by the invention may be in the form of an eye drop, an ointment or a gel and may also contain pharmaceutically acceptable excipients.
• FIG. 1 represents a fluorescence peak, typical and representative of the inflammation of conjunctival cells, emitted by the DNA of conjunctival cells, this peak being obtained by analysis in flow cytofluorometry, and
• the affections of the ocular surface concerned by the invention can be due to: - exposure to environmental agents such as city photochemical mists (ozone, nitrogen oxides, sulfur dioxide, volatile organic compounds, diesel particles),
• UVs A, B, C ultraviolet
• X-rays X-rays
• ⁇ rays radioactive radiation
• the pharmaceutical composition obtained by the use of these antioxidants will therefore contain, as active ingredient, one or more antioxidants and pharmaceutical excipients acceptable for local application in the eye.
• antioxidants are superoxide dismutases, mimics of superoxide dismutases, derivatives of superoxide dismutases, racemic alpha lipoic acid or its enantiomers
• SODs superoxides dismutases also called SODs, represent one of the three main classes of antioxidant enzymes with catalase and glutathione peroxidase in the body (Fridovich 1986).
• Superoxide dismutases or SODs are antioxidant metallo-enzymes discovered in 1969 by Me Cord and Fridovich, capable of catalyzing the dismutation reaction of the superoxide anion (0 2 .-) into peroxide of hydrogen (H 2 0 2 ) and of oxygen in an aqueous medium according to the following reaction, which requires the presence of iron.
• Cu / Zn SODs usually located in the cytosol of eukaryotic cells, in the extracellular fluid of mammals and in certain bacteria, the Mn SODs in prokaryotes or in the mitochondria and Fe SODs containing iron, localized in anaerobic bacteria and prokaryotes.
• the Cu / Zn SODs group together the Cu / Zn SODs I and I
• human Cu / Zn SOD in recombinant form
• Cu / Zn SODs from plants either extraction, wheat, melon, tomato, pollen , spinach or rice, either recombinant.
• Cu / Zn SODs of bacterial extraction including that of Saccharomyces Cerevisae and Cu / Zn SODs of animal extraction of bovine and Cu / Zn SODs of recombination.
• the Mn SODs group together the Mn SODs I and II which exist in the form of extraction or recombinant.
• Fe SODs exist in extracted or recombinant form.
• Cu / Zn SODs are more particularly preferred for use in the invention.
• SODs are enzymes with a molecular point of 32 kd. They are composed of two subunits, each containing a copper and zinc atom, linked noncovalently (Relier GA et al. 1991).
• the complexes mimicking the effects of the different SODs at the extra or intra cellular level that is to say the mimetics of SODs are also compounds which are particularly preferred in the invention because they have better permeability and stability.
• trans-bis (naproxenato) bis (3-Pyridylmethanol) monomeric copper II complexes derived from bioflavonoids such as rutin containing iron and copper, 1, 4, 7, 10, 13-pentoazacyclopentadecane, and SODase are particularly preferred.
• heterologous SODs appear to exhibit significantly higher anti-inflammatory activity than the homologs.
• These heterologous SODs which have a low incidence of immunological nature, do not induce a proinflammatory reaction and protect the cells from degeneration by inhibiting the formation of oxygenated free radicals. Consequently, the present invention proposes, because of the positive effects of SOD, to use it alone or in the presence of a pharmaceutical vehicle in the treatment of affections of the ocular surface.
• SODs are molecules that are quickly eliminated from the cornea by tears. They cannot thus exert their full action when instilled in the eye.
• the invention proposes to use as antioxidant alpha-lipoic acid and / or one of its R + or R " enantiomers.
• Alpha lipoic acid discovered in 1937 and chemically characterized by Lester Reed in 1951, is known by a variety of names including 2-dithiolane-3 pentanoic acid, valeric acid 1,2 dithiolane 3, l thioctic acid. It is an antioxidant synthesized by the human body but also present in small quantities in potatoes, spinach and red meat.
• alpha lipoic acid is a racemic form (alpha lipoic RAC, alpha lipoic DL) but it is also active by its R + or R " enantiomers. The most active is R + alpha lipoic acid or R- acid. thioctic or alpha lipoic acid R, dexlipotam 1200 22 2.
• Alpha lipoic acid and its derivatives can thus be in the form of multiple chemical complexes.
• DHLA dihydrolipoate
• LA / DHLA can: - trap free radicals (hydroxyl radical OH., Hypochlorous acid HCLO, oxygen singuletO2, - chelate metals (stable complexes with Cu 2+ , Mn 2+ and Zn 2+ ), - regenerate the oxidized forms of vitamins E, C, glutathione and thioredoxin. In its presence, there is an increase in glutathione in the cells,
• DHLA also protects from the deleterious effects of ischemia-reperfusion by inhibiting the activity of xanthine oxidase, an enzyme that releases superoxide anion (Prenn JH et al. 1990, 1992, Scheer B. and Zimmer G. 1993, Serbinova E. et al. 1992).
• racemic alpha lipoic acid and its enantiomers are particularly advantageous active ingredients for treating and / or preventing surface eye conditions in humans or animals.
• alpha-lipoic acid and its enantiomers alone or in combination with one another and, on the other hand, superoxide dismutases, alone or in combination with one another, have been found to be excellent active ingredients for the treatment of ocular surface conditions in humans and animals, it is advantageous to use alpha lipoic acid in combination with one or more of the above-mentioned superoxide dismutases.
• SODs and alpha lipoic acid are particularly effective active ingredients, to be introduced into a pharmaceutical composition, for the treatment or prevention of affections of the ocular surface.
• the tests are carried out by cytofiuorometric microtitration in cold light.
• This new technique makes it possible by purifying the heat energy of the illumination system (infrared and Joule effect) to obtain very low background noise and therefore to have a good signal / noise ratio and good sensitivity. It combines the reproducibility of microplate methods with the sensitivity of cytometric methods, with a very wide detection spectrum (280-870 nm).
• the microplate is scanned by a light brush of defined wavelength which illuminates each culture well for less than 0.3 seconds, which limits any phenomenon of extinction of the probes.
• Dichlorofluorescein diacetate test Corneal and / or conjunctival cells of human origin in culture are exposed to various environmental agents to induce the release of free radicals.
• the active compounds of the invention Cu / Zn SOD or alpha-lipoic acid
• the fluorogenic probe becomes fluorescent when it binds to hydrogen peroxide.
• the DCFH-DA solution used is a 20 ⁇ m solution in minimum modified essential medium from Dulbecco (DMEM).
• DMEM Dulbecco
• the cultures are then placed for 20 minutes in DMEM containing the probe and then they are extracted in order to measure the production of hydrogen peroxide. The measurement is made directly on the cells in 96-well plates (Debbasch C. et al. 2000).
• Corneal and conjunctival cells of human origin in culture, exposed to various attacking agents to induce the release of free radicals are treated or not with the active compounds of the present invention (Cu / Zn SOD or alpha-lipoic acid) at different concentrations.
• the hydroethidine solution used is a 5 ⁇ m solution.
• the cell cultures are placed for 10 minutes in DMEM containing the probe and then the cells are extracted in order to measure the production of superoxide anion. The measurement is made in 96-well microplates. The analyzes are thus carried out on 5000 cells per well, each measurement being repeated six times. The results are expressed in fluorescence units. The mean fluorescence values are calculated in each group and compared by a non-parametric Mann-Whitney U test.
• the active compounds of the invention significantly reduce the toxicity of benzalkonium chloride on the cells conjunctival in culture.
• the active compounds of the invention reduce epithelial erosion.
• quaternary ammoniums and in particular benzalkonium chloride are present in the vast majority of eye drops, gels and eye ointments, as preservatives.
• the compounds of the invention which make it possible to counteract the harmful side effects of these preservatives, can therefore be used not only as active principles for curing the affections of the ocular surface already installed, but also as additives to other active ingredients for preventing the side effects of preservatives, both of the quaternary aluminum type and of all the other preservatives which can cause the formation of oxygenated free radicals and therefore apoptosis phenomena, present in the pharmaceutical composition administered.
• SODs as well as alpha lipoic acid and their mixtures are useful both for curing and for preventing diseases of the ocular surface.
• the apoptosis induced by benzalkonium chloride was chosen as the model for ocular surface conditions treated and / or prevented by the invention.
• This apoptosis study is carried out by comparing, by flow cytofluorometry, the percentage of DNA in sub-Gl phase obtained before and after treatment with the compounds of the invention.
• Apoptosis is characterized by a fragmentation of DNA into identical fragments of 200 basic people.
• the cells involved in this process therefore have a reduced DNA content.
• This DNA fragmentation can be measured in situ by flow cytofluorimetry with a DNA dye, propidium iodide.
• the reduced DNA appears with a lower fluorescence intensity than that of normal cells.
• cytofluorimetry a peak is obtained as shown in FIG. 1.
• this peak is divided into three zones denoted M1, peak Gl and phase S and G2M.
• the number of normal cells appears in the area of peak Gl.
• cells having a lower fluorescence intensity that is to say those whose DNA has been fragmented, appear below this Gl peak, that is to say in that 'is called the sub-Gl peak located in the area denoted Ml in Figure 1.
• Apoptosis was induced by adding 0.001%, by volume relative to the total volume of the sample, of benzalkonium chloride (BAC) in the culture medium D-MEM (modified Eagle medium from Dulbecco: references 21885, GibcoBRL products; enriched with 10%, by volume relative to the total volume of the sample, of fetal calf serum and supplemented with 50 mg / ml of streptomycin and 50IU / ml of penicillin) in which conjunctival cells are cultured, in 6-well plates.
• D-MEM modified Eagle medium from Dulbecco: references 21885, GibcoBRL products; enriched with 10%, by volume relative to the total volume of the sample, of fetal calf serum and supplemented with 50 mg / ml of streptomycin and 50IU / ml of penicillin
• conjunctival cells were cultured in the culture medium described above and, at 80% confluence, SOD, alpha-lipoic acid and their associations were
• benzalkonium chloride was added to each well. After 15 minutes of incubation, the supernatants from each well were collected in 15 ml tubes; the cells were detached by the action of 0.25% trypsin for 5 minutes at 37 ° C. and added to their respective supernatants. The tubes were then centrifuged, then the cells were washed twice in phosphate buffer. The cell pellet was resuspended in phosphate buffer at a concentration of 1 million cells per milliliter.
• BAC benzalkonium chloride
• BAC benzalkonium chloride
• FIG. 2 on the left side are represented the histograms corresponding to the controls and on the right side the histograms corresponding to the cells on which apoptosis has been induced by the addition of benzalkonium chloride (BAC).
• BAC benzalkonium chloride
• apha-lipoic acid has a healing effect, and therefore a prevention effect, more important than SOD, and this at much lower concentrations than those of SOD.
• SODs are giant molecules and that alpha lipoic acid is a smaller molecule which would fit into the spaces between the different SOD molecules and which would thus form a particularly effective association with SOD.
• compositions containing between 1 ⁇ g / ml to 500 ⁇ g / ml of SOD, preferably containing 25 at 50 ⁇ g / ml SOD for administration by instillation into the eye are very effective.
• compositions containing racemic alpha-lipoic acid or one of its enantiomers will advantageously be used at concentrations between 0.05 ⁇ g / ml to 200 ⁇ g / ml in a pharmaceutical composition for instillation into the eye.
• the compositions will contain between 0.05 ⁇ g / ml and 5 ⁇ g / ml of racemic alpha-lipoic acid and / or one of these enantiomers.
• compositions for the treatment and / or prevention of affections of the ocular surface will contain a mixture of SOD or SOD derivatives or mimetics at the concentrations mentioned above for SOD alone, and alpha- racemic lipoic or in the form of its R + , R " enantiomers at the concentrations cited above for the compositions containing alpha-lipoic acid alone.

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