Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
  • A61K9/0051—Ocular inserts, ocular implants
• • 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
  • A61P27/14—Decongestants or antiallergics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
  • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
  • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups

Definitions

• the present invention relates to a new therapeutic use of the compounds of formula (I) as defined below.
• the present invention relates to the use of these compounds and their pharmaceutically acceptable salts for the treatment and / or prevention of ocular inflammatory diseases, and more particularly of uveitis, of severe conjunctivitis (vernal keratoconjunctivitis). , dry eye syndrome (keratoconjunctivitis sicca) and diabetic retinopathy.
• Inflammatory eye diseases are the leading cause of impaired vision in the world.
• uveitis refers to inflammation of the uvea, the middle vascular layer of the eye consisting of the iris, ciliary body, and choroid. Inflammation in uveitis results from a wide variety of traumatic and immune-mediated aggression.
• Conjunctivitis includes diseases characterized by swelling, itching or burning, or redness of the conjunctiva, a membrane covering the whiteness of the eye.
• the etiology of conjunctivitis includes infectious and noninfectious conjunctivitis.
• Conjunctivitis is typically acute in the case of bacterial or viral infections and chronic in the case of allergy.
• Dry eye syndrome is one of the most common eye diseases. It is also called keratoconjunctivitis sicca (KCS). It is characterized by symptoms of eye irritation and may cause a disturbed vision, which increases the risk of infection and corneal ulceration. The pathogenesis of dry eye is not fully understood, although it is widely accepted that dry eye is associated with inflammation of the ocular surface.
• KCS keratoconjunctivitis sicca
• Diabetic retinopathy is a consequence of chronic hyperglycemia, resulting in capillary lesions with functional changes such as edema and ischemia.
• Laser photocoagulation is still the treatment of reference, and vitrectomy is used in case of detachment of the retina.
• Lucentis® (Ranibizumab) is used to treat macular edema.
• corticosteroids administered locally or systemically. Nevertheless, corticosteroids have serious side effects both systemically and locally, such as corticosonic cataract, corticosonic glaucoma, superinfection and delayed healing.
• Non-steroidal anti-inflammatory agents such as Diclofenac or Flurbiprofen.
• Diclofenac or Flurbiprofen.
• many subjects do not react or become refractory to steroidal or nonsteroidal therapy.
• antimetabolite drugs such as Azathioprine and Methotrexate with hematologic and hepatic toxicities primarily used to treat recurrent and very severe uveitis
• immunosuppressants such as orally administered Cyclosporine A and Tacrolimus, which also have many side effects, such as risk of impaired renal function, increased risk of lymphoproliferative disorders and malignant skin tumors.
• these immunosuppressants can be used topically but, given their macrocyclic structures, these compounds are not soluble in aqueous media. They are formulated especially in oily vehicles with the disadvantage of being irritating, painful and cause a disturbance of vision. In the end these compounds are poorly tolerated by the subjects.
• the present invention overcomes the disadvantages of the state of the art by providing a new use of one or more compounds of formula (I) and their pharmaceutically acceptable salts and, in particular, their use in the treatment and / or prevention ocular inflammatory diseases such as uveitis, severe conjunctivitis, dry eye syndrome or diabetic retinopathy.
• the present invention provides aqueous pharmaceutical compositions containing the compounds of formula (I), which allow to reach the posterior chamber of the eye, which represents a considerable advance for the treatment of inflammatory ocular diseases.
• the compounds of the present invention have little or no effect on the systemic immune response, thereby significantly limiting the potential side effects associated with the administration of said compounds.
• the present invention is based on the unexpected results demonstrating that the compounds of formula (I) (hereinafter referred to as "compounds of the invention”) and their pharmaceutically acceptable salts are capable, when administered locally, to improve the clinical signs in the uveitis models, with in particular protection of the ocular and ocular barriers of the anterior and posterior chamber without modification of the systemic immune response. Similarly, the compounds of the invention are also useful for the treatment of severe conjunctivitis, dry eye syndrome and diabetic retinopathy.
• the compounds of the invention and their pharmaceutically acceptable salts, with their linear structure, are soluble and stable in aqueous media, so that they can be administered locally in aqueous formulations that are perfectly biocompatible and do not cause irritation or impaired vision.
• the present invention thus relates to the use of the compounds of the invention and their pharmaceutically acceptable salts, in particular Tresperimus and Anisperimus, for the preparation of a medicament useful for the treatment and / or prevention of inflammatory eye diseases, in uveitis, severe conjunctivitis, dry eye syndrome or diabetic retinopathy.
• the present invention provides a method for treating and / or preventing eye inflammatory diseases, including uveitis, severe conjunctivitis, dry eye syndrome or diabetic retinopathy, comprising: administering to a subject in need thereof one or more compounds of the invention or a pharmaceutically acceptable salt thereof.
• the compound of the invention or its pharmaceutically acceptable salt is Tresperimus or Anisperimus.
• the compound (s) of the invention may be administered locally.
• the compound (s) of the invention are administered in the form of eye drops or in the form of an injectable solution intraocularly or periocularly, or of an implantable system.
• the compounds of the invention and their pharmaceutically acceptable salts are particularly useful for the treatment and / or prevention of uveitis, dry eye syndrome or diabetic retinopathy. .
• the present invention relates to suitable formulations of a pharmaceutical composition
• a pharmaceutical composition comprising as sole active ingredient a compound of the invention or a pharmaceutically acceptable salt thereof for topical administration to subjects having inflammatory eye diseases.
• a pharmaceutically acceptable aqueous formulation for local administration.
• the compounds of the invention in particular Tresperimus and Anisperimus, or their pharmaceutically acceptable salts, may be administered in combination with an anti-VEGF, an anti-TNF, a corticosteroid, a nonsteroidal anti-inflammatory agent, an antibiotic or an immunosuppressant.
• Figure 1 shows the effect of a Tresperimus injection on clinical autoimmune uveoretinitis (UAE) in rats.
• Figure 2 shows the effect of an intravitreal injection (IT) of Tresperimus on the histopathological scores of UAE (A) and the histopathological changes of UAE in rats treated with Tresperimus (C) compared with rats subjected to saline injection (B).
• I intravitreal injection
• A histopathological scores of UAE
• C histopathological changes of UAE in rats treated with Tresperimus
• B saline injection
• FIG. 3 shows the effect of Tresperimus in the S-specific delayed-type hypersensitivity (HTR) in rats treated with intravitreal injection.
• Figure 4 shows the ocular distribution of Tresperimus after instillation of eye drops of a 1% solution twice daily for 4 days in male New Zealand rabbit.
• Figure 5 shows the effect of Tresperimus after treatment with instillations on the clinical signs of LPS-induced uveitis (lipopolysaccharide).
• Figure 6 shows the effect of Tresperimus after instillation treatment on the number of infiltrating inflammatory cells in LPS-induced uveitis.
• Figure 7 shows the effect of Tresperimus on the tear volume measured by the phenol red test.
• Figure 8 shows the effect of Tresperimus on the stability of the tear film as measured by tear film rupture time.
• Figure 9 shows the effect of Tresperimus on the production of MCP-1 and IL-6 in vitreous.
• Figure 10 shows the effect of Tresperimus on the amplitude of pseudo-oscillations at different frequencies.
• the "subject” is preferably a mammal, more preferably a human.
• Prevention and / or treatment method shall be understood as covering those processes in which a compound or derivative or salt thereof is administered for the treatment and / or prevention of the specified disease.
• Inflammatory eye diseases is a general term for inflammation affecting any part of the eye or surrounding tissue. Inflammation involving the eye can range from familiar allergic conjunctivitis of hay fever to rare conditions potentially leading to blindness such as severe conjunctivitis (vernal keratoconjunctivitis), uveitis, scleritis, episcleritis, neuritis keratitis, retrobulbar pseudotumor, Eales syndrome, dry eye syndrome, diabetic retinopathy, age-related macular degeneration (AMD), an ocular manifestation of a systemic ocular tissues, that is to say the retina, which can ultimately lead to blindness.
• the localization of inflammation governs the diagnostic designation of inflammatory ocular disease. Inflammatory eye diseases can result from several causes.
• uveitis is non-infectious and comes from traumatic, drug-induced causes, immune-mediated causes, malignant causes, or causes following ophthalmic surgery.
• compositions of the present invention may also be used after ophthalmic surgery causing ocular inflammation such as corneal transplantation.
• Uveitis refers to the inflammation of the uvea, the middle vascular layer of the eye consisting of the iris, ciliary body and choroid. It is classified according to its location, its clinical evolution and its laterality. "Anterior” refers to the involvement of the iris, cornea, pupil, aqueous humor or ciliary body. For example, we can mention as anterior uveitis Kawasaki disease.
• Intermediate refers to the vitreous, the posterior zone of the ciliary body, the peripheral retina and the sclera.
• Noninfectious posterior uveitis includes Behcet's disease, Vogt-Koyanagi-Harada's disease, inflammation of the posterior zone of the ciliary body, sarcoidosis, idiopathic retinal vasculitis and multifocal inflammation of the retina. and the choroid.
• Pantuheite is used when two or more segments are affected.
• the conjunctivitis is non-infectious and comes mainly from severe ocular allergies since it sometimes leads to ulcerations that always involve a risk of significant and permanent visual losses.
• Allergic conjunctivitis is an inflammatory reaction of the conjunctiva (a thin membrane that covers the eye and the inside of the eyelid).
• the eyes can become red, tingling, burning, scratching, itching and watering.
• the light is difficult to bear (photophobia).
• the eyelids are often red and swollen, and sometimes the swelling of the conjunctiva (chemosis), or even a darker marking of the contours of the eyes or important secretions of mucus. It affects little the cornea. It is the most common and probably the least serious form of ocular allergy. This type I reaction is often the result of pollen abundance in spring and summer (tree and grass pollen).
• the term allergic keratoconjunctivitis is used when the damage also affects the cornea and not just the conjunctiva.
• vernal conjunctivitis is a serious form of ocular allergy since it sometimes leads to ulcerations that always involve a risk of significant and permanent visual loss. These ulcerations are often located in the upper part of the cornea and papillae form on the conjunctiva, especially on the upper eyelid.
• Dry eye or kerato-conjunctivitis dry eye syndrome refers to all eye conditions resulting from secretion by the lacrimal glands of tears in an inadequate quantity or quality.
• dry eye syndrome also relates to all tear-deficient forms (including autoimmune dry eye Sjogren's syndrome and non-Sjogren's tear deficiency) and evaporative forms. Dry eyes are also recognized as the disruption of the lacrimal functional unit, an integrated system comprising the lacrimal glands, the ocular surface (cornea, conjunctiva and meibomian glands) and the eyelids, as well as the sensory nerves that connect them.
• Diabetic retinopathy refers to damage to the retinal and choroid microcirculation (affected organs are the retina, choroid, papilla and iris) due to chronic hyperglycemia. There are two forms: simple (or non-proliferative) and proliferative.
• retinal and usually macular edema there is an appearance of retinal and usually macular edema.
• occlusions of the retinal capillaries occur causing retinal ischemia.
• these two major characteristics can be associated and lead to ischemia in the retinal periphery and macular exudates.
• the compounds of the invention are also useful in the treatment of age-related macular degeneration (AMD).
• AMD age-related macular degeneration
• n is equal to 6 or 8
• A is a bond, a CH 2 group, a CH (OH) group, a CHF group, a CH (OCH 3 ) group, a CH 2 NH group or a CH 2 O group;
• - R is a hydrogen atom or a CH 3 .
• salts of the compounds of the invention can be obtained by chemical reaction between an inorganic or organic acid and the compounds of formula (I) mentioned below.
• the preferred inorganic acids for the formation of salts are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid.
• the preferred organic acids for the formation of salts are: fumaric acid, maleic acid, oxalic acid, citric acid, trifluoroacetic acid, tartaric acid and sulphonic acids (methanesulphonic acid). with dodecane sulphonic acid).
• the compounds of formula (I) are advantageously chosen from: 2 - [[6- [(aminoiminomethyl) amino] hexyl] amino N- [4 - [(3-aminopropyl) amino] butyl] -carbamate -2- oxoethyl;
• the compounds of formula (I) which are particularly preferred are 2- [[6 - [(aminoiminomethyl) amino] hexyl] amino N- [4 - [(3-aminopropyl) amino] butylcarbamate] - 2-oxoethyl, and 2 - [[6- [(aminoiminomethyl) amino] hexyl] amino] -2-oxoethyl N- [4 - [(3-aminobutyl) amino] butylcarbamate tetrachloride.
• compositions of the invention typically comprise a compound of the invention or a pharmaceutically acceptable salt thereof as the only active substance, as well as one or more pharmaceutically acceptable carriers or excipients.
• “Pharmaceutical vectors” refers to an excipient or a mixture of a plurality of pharmaceutically acceptable excipients which allow the administration of active substances. They allow and can facilitate or improve the preparation of the composition and can stabilize the composition. In addition, the pharmaceutically acceptable vectors can increase the effectiveness of the composition, improve the ocular tolerability of the active substance and / or modify its release profile.
• Such vectors may take a wide variety of forms depending on the form of preparation desired for administration, for example local administration.
• “Local administration” should be understood as defining all ocular pathways, ie topical, injectable administrations or administrations using implantable systems.
• Topical administration can be in form, for example and without limitation, eye drops or eye drops or instillations eyepieces, sprays, creams, ointments, gels, hydrogels, oieogels, hydrophilic lenses, inserts and implants.
• the galenic forms may be, for example and without limitation, solutions, suspensions, colloidal systems (for example liposomes, emulsions, microemulsions, nanoemulsions, microparticles, nanoparticles, microspheres, niosomes, dendrimers), micelles, mixed micelles, complexing systems, for example cyclodextrin solutions, and also non-implantable inserts in the form, for example and without limitation of disks, films or lamellae.
• colloidal systems for example liposomes, emulsions, microemulsions, nanoemulsions, microparticles, nanoparticles, microspheres, niosomes, dendrimers
• micelles mixed micelles,
• Intravitreal administration may be non-restrictively in intraocular (intravitreal, IVT), periocular including subconjunctival administration, under the Tenon capsule, retrobulbar and intrasclerotic.
• “Intravitreal administration” can be performed as injectable or implantable systems.
• the galenic forms may be in a nonlimiting manner solutions, suspensions, colloidal systems (for example liposomes, emulsions, microemulsions, nanoemulsions, microparticles, nanoparticles, microspheres, niosomes, dendrimers), micelles, mixed micelles, and also implants biodegradable or non-biodegradable form, for example and without limitation rods, nails, pellets.
• most of the dosage forms mentioned above can potentially increase the residence time of the active ingredient on the surface of the eye or in the vitreous, allow slow and prolonged release of encapsulated compounds and / or avoid toxicity and increase ocular tolerability.
• the compounds of the invention or their pharmaceutically acceptable salts can be administered via a pharmaceutically acceptable, aqueous composition and formulation adapted to a particular topical administration, preferably by instillation, or injectable administration, preferentially intravitreal.
• the excipient (s) For topical or injectable administration, the excipient (s) must be pharmaceutically acceptable and suitable for this type of ocular administration.
• the aqueous media used in the present invention consist of water containing no physiologically and ophthalmologically harmful agents.
• the pharmaceutical composition according to the invention is in the form of an aqueous pH formulation that is physiologically compatible for the ocular route.
• physiologically compatible pH for the ocular route means a pH in the range of about 5.5 to about 8, preferably about 6.0 to about 7.5.
• the pH of the preparations is adjusted with an acid such as, for example, acetic acid, boric acid, lactic acid and hydrochloric acid; a base such as, for example, sodium hydroxide, sodium borate, sodium citrate, sodium acetate; or a pharmaceutically acceptable buffered solution, such as, for example, sodium phosphate buffer, potassium phosphate buffer, sodium citrate buffer.
• the aqueous preparations according to the invention are isotonic and physiologically suitable for topical and intraocular ocular administrations.
• the osmotic pressure of the preparations is close to the physiological pressure and is generally between about 200 mOsm and about 400 mOsm, preferably between about 260 and about 340 mOsm.
• the osmotic pressure can be adjusted using appropriate amounts of physiologically and ophthalmologically acceptable excipients.
• Sodium chloride is generally used as a tonicity agent at a concentration (expressed in m / V) not exceeding 0.9%.
• Equivalent amounts of one or more salts composed of a cation and an anion may also be employed.
• the osmotic pressure can be corrected by adding sugars or polyols, alone or in combination.
• the preparations of the present invention have a variable viscosity of from 0 to about 2000 Centipoises, preferably less than about 100 Centipoises, and more preferably less than about 30 Centipoises.
• composition of the present invention may contain viscosity increasing agents to prolong the premorneal residence time of the active ingredient after instillation.
• these viscosifying agents may have mucoadhesive properties.
• Mucoadhesive polymers capable of creating non-covalent bonds with the glycoproteins present in particular at the conjunctival level can be used in the present invention to restrict the formulation locally to the eye, in order to optimize the residence time of the formulation locally and potentially to increase the bioavailability of the active principle at the ocular level, reduce the frequency of administration and thus improve the therapeutic compliance. These polymers are generally macromolecular hydrocolloids.
• cellulose derivatives such as methylcelluloses, sodium carboxymethylcelluloses, hydroxyethylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses, acrylic derivatives such as, for example, polyacrylic acid salts and its functionalized (or polycarbophilic) derivatives, carbomers, products of natural origin such as, for example, alginates, chitosans, pectins, hyaluronic acid and its derivatives, polysaccharide derivatives such as, for example, gellan gum and its derivatives, xanthine gum, carrageenans, co-polymers such as for example poloxamers.
• cellulose derivatives such as methylcelluloses, sodium carboxymethylcelluloses, hydroxyethylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses
• acrylic derivatives such as, for example, polyacrylic acid salts and its functionalized (or polycarbophilic) derivatives
• carbomers products of natural origin such as, for example,
• Polymers having in situ gelling ability may be included in the preparation of the pharmaceutical composition of the invention.
• phase transition systems are liquid and result in the formation of gels compatible with ocular functions by ionic activation, as a function of pH or temperature.
• examples that may be mentioned include polymers such as polyacrylic acid derivatives, carbomers, cellulose derivatives, methylcelluloses, copolymers and poloxamers.
• composition of the present invention may also contain, for example, surfactants, cosolvents, penetrating agents, gelling agents, emulsifiers, antioxidants, preservatives, polymers for sustained release, excipients which are well known in the art. skilled person.
• the pharmaceutical composition may also be in the form of an insert or a solid implant allowing ocular administration and prolonged release of the active ingredient.
• the insert preparation can be performed using a water-soluble solid polymer.
• Biocompatible polymers for the ocular route, inert, used for the preparation of an insert adapted to the ocular route are synthetic, semi-synthetic or of natural origin.
• composition of the solid implants may also be constituted by synthetic, semi-synthetic or naturally occurring polymers, preferably by biodegradable polymers such as, for example, polyvinyl alcohols, polylactic-co-glycolic acids, poly-epsilon-caprolactones. hyaluronic acid esters.
• biodegradable polymers such as, for example, polyvinyl alcohols, polylactic-co-glycolic acids, poly-epsilon-caprolactones. hyaluronic acid esters.
• biodegradable polymers can also be used for the encapsulation of the active ingredient in microspheres, nanospheres, microcapsules, nanocapsules dispersed in aqueous solution for sustained and targeted release of the active ingredient.
• matrices such as water-soluble lenses impregnated or containing the active ingredient may make it possible to increase the residence time of the active ingredient on the surface of the eye.
• the pharmaceutical composition in the form of eye drops or injectable solution comprises an effective dose of a compound of the invention such as, for example Tresperimus, dissolved in a physiological aqueous solution as the main vector.
• a compound of the invention such as, for example Tresperimus
• This solution ideally comprises an aqueous solution of sodium chloride at a concentration preferably not exceeding 0.9% (w / v), or an aqueous glycerol solution at a concentration not exceeding preferably 2.5% ( m / V) and this in order to obtain a tonicity of the pharmaceutical composition of between about 260 and about 340 mOsm.
• This solution is adjusted to a pH of about 6.5 using, for example, sodium hydroxide.
• a bioadhesive polymer such as preferentially hyaluronic acid or a derivative thereof is added.
• This galenic form is sterilized preferably by gamma ray treatment.
• This galenic manufacture can be packaged in a single dose form.
• the injectable solution for administration in the form of a biodegradable implant comprises an effective dose of at least one compound of the invention encapsulated preferably in micro- or nanoparticles consisting of poly-epsilon-caprolactones. .
• a major advantage of the present invention is that all ocular tissues (anterior or posterior chambers) are exposed to the compounds of the invention, for example by administering a pharmaceutically acceptable aqueous composition.
• Figure 4 In an ocular distribution study in male New Zealand rabbit ( Figure 4) with Tresperimus after instillation of eye drops of a 1% solution twice daily for 4 days, it was observed that the retina / choroid (posterior chamber) and the ciliary body / iris (anterior chamber) were exposed to Tresperimus levels of 0.5 to 0.7 ⁇ and 0.3 to 0.7 ⁇ for 24 h after repeated instillation of eye drops twice daily in the form of a simple 1% aqueous solution.
• the topical administration of the compounds of the invention may allow a much better control of the concentrations of active substance. in ocular tissues.
• plasma levels were found to be low ( ⁇ 50 ng / mL from 5 min to 2 h after instillation) and for a short time below the lower limit of quantification (Blq) (2 ng / mL 4 hours after the dose) after instillation of eye drops. This makes it possible to avoid the undesired effects of immunosuppression at the systemic level.
• the concentration of the therapeutically active substance in the formulations intended for the intravitreal route may vary from 0.1 ⁇ to 100 m, preferably from 1 ⁇ to 10 m, and more preferably from 10 ⁇ to 0.1 mM.
• the concentration of the therapeutically active substance in the formulations for ocular topical instillation can vary from 0.001% to 5% (expressed in m / V), and preferably from 0.001% to 1.5%, more preferably from 0.01% to 1%. , 5%. These concentrations can be applied for other local routes of administration ocular and may vary depending on the therapeutic indication, it is left to the discretion of the practitioner mode of administration and dosage according to the subject, its symptoms and the degree of severity of his pathology.
• compositions are prepared by any galenic manufacturing process well known in the field of pharmaceutical techniques.
• the compound (s) of the present invention may be combined with or used in combination with other therapeutic agents.
• a subject may be treated with one or more compounds of the invention or a pharmaceutically acceptable salt thereof, particularly Tresperimus and / or Anisperimus, together with other conventional drugs for the treatment of inflammatory eye diseases.
• the administration of the different active substances can be simultaneous, sequential or spaced apart over time.
• the compound of the invention or a pharmaceutically acceptable salt thereof will not be administered together with an inhibitor of the Lck enzyme.
• the present invention therefore relates to a pharmaceutical composition
• a pharmaceutical composition comprising, as active substances, at least one compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more drugs used in the treatment of uveitis, chosen from corticosteroids such as, for example, dexamethasone, prednisolone and triamcinolone; immunosuppressants having a mechanism of action different from the compounds of the invention such as, for example, cyclophosphamide, methotrexate, azathioprine, cyclosporin A, tacrolimus, sirolimus, mycophenolate mofetil; anti-TNF such as, for example, Rituximab, Daclizumab, Infliximab, Adalimumab and Etanercept.
• corticosteroids such as, for example, dexamethasone, prednisolone and triamcinolone
• immunosuppressants having a mechanism of action different from the compounds of
• the present invention therefore relates to a pharmaceutical composition
• a pharmaceutical composition comprising, as active substances, at least one compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more drugs used in the treatment of severe conjunctivitis, chosen from corticosteroids such as for example Dexamethasone, Prednisolone; nonsteroidal anti-inflammatory drugs such as Nedocromil, Iodoxamide, Olopatadine; antibiotics, antifungals and anti-bacterials such as Tobramycin, Natamycin, Moxifloxacin; immunosuppressants having a mechanism of action different from the compounds of the invention such as, for example, Cyclosporin A, Tacrolimus, Sirolimus;
• corticosteroids such as for example Dexamethasone, Prednisolone
• nonsteroidal anti-inflammatory drugs such as Nedocromil, Iodoxamide, Olopatadine
• antibiotics, antifungals and anti-bacterials such as Tobramycin, Natamycin, Mo
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising, as active substances, at least one compound of the invention or a pharmaceutically acceptable salt thereof in combination with one or more drugs used in the treatment.
• dry eye syndrome chosen from immunosuppressants having a mechanism of action different from the compounds of the invention such as, for example, Cyclosporin A and Mycophenolate mofetil; corticosteroids such as, for example, Loteprednol, Rimoxelone and Fluorometholone; and the Tetracyclines. They can also be used in combination with artificial tears and secretagogues.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising, as active substances, at least one compound of the invention or a pharmaceutically acceptable salt thereof in combination with one or more drugs used in the treatment.
• diabetic retinopathy selected from anti-VEGF such as for example Ranibizumab, Pegatapnib, Bevacizumab; anti-TNF agents such as, for example, Rituximab, Daclizumab, Infliximab, Adalimumab and Etanercept; corticosteroids such as, for example, Dexamethasone, Prednisolone and Triamcinolone; and immunosuppressants having a mechanism of action different from the compounds of the invention such as, for example, Cyclosporin A, Tacrolimus, Everolimus and Sirolimus. They can also be used in combination with laser therapy (photocoagulation).
• anti-VEGF such as for example Ranibizumab, Pegatapnib, Bevacizumab
• the eye is a site of immunological privilege nevertheless diseases of the eye coming from an imbalance of the immune system develop and are responsible for impairments of vision that can go as far as blindness.
• Animal models mainly experimental autoimmune uveitis (UAE) and endotoxin-induced uveitis (UIE), are considered clinically relevant models of ocular diseases and are valuable tools for the study of immunological mechanisms for regulation. diseases in humans:
• the rat-induced KRA by immunization with purified antigens of the retina mainly the S antigen (Ag-S) is considered as a clinically relevant model for the study of the mechanisms of posterior uveitis in humans and the development of new therapeutic strategies for uveitis
• UIE is a model of acute inflammatory uveitis, spontaneously resolving, involving components of the innate immune system. It is a useful model for the study of local aspects of ocular inflammation and is considered a relevant model of anterior uveitis in humans.
• the UAE models help to understand the physiopathological mechanisms and in particular the involvement of CD4 + lymphocytes (cluster of differentiation 4), macrophages and proinflammatory cytokines in the mechanisms of destruction of the retina.
• the UAE is a model of inflammatory disease that shares many clinical and histopathological features with human uveitis such as sympathetic ophthalmia, birdshot retinochoroidopathy, Vogt-Koyanagi-Harada syndrome, Behcet's disease, and sarcoidosis. It is a clinically relevant model for human eye inflammation.
• the UAE is induced by immunization with purified retinal autoantigen, S antigen (S-Ag) which is also recognized by subjects with uveitis.
• S-Ag S antigen
• the UAE is dependent on Th1 effector cells (interferon-gamma producing cells) and Th17 (interleukin-17 producing cells) CD4 +, each effector phenotype can induce a pathological reaction.
• IL-17 interleukin-17 plays a preponderant role in the UAE induced by the IRBP protein (interphotoreceptor retinoid-binding protein, in French retinol-binding protein inter-photoreceptors).
• the neutralization of ITL-17 prevents or reverses the disease.
• the Thl7 effector cells induce a UAE in the absence of interferon (IFN) -gamma.
• IFN interferon
• Macrophages cross the blood-retinal barrier and infiltrate the retina, where the release of mediators such as NO (nitric oxide) and TNF (tumor necrosis factor) can cause severe retinal damage and, consequently, vision loss in patients. topics.
• Tresperimus was performed by intravitreous (IVT) injections (5 ⁇ L) in both eyes on days 6, 9 and 12 after immunization with S-Ag.
• IVT intravitreous
• the rats were anesthetized by intraperitoneal injection of pentobarbital (Sanofi-Aventis, France) prior to blood collection by intracardiac puncture.
• pentobarbital Sanofi-Aventis, France
• a group of rats received a sterile, substantially isoosmolar and physiological saline solution at 9 mM Tresperimus to obtain a final solution at 1 mM in the vitreous
• a control group of rats received a vehicle (saline) and a control group of rats was not treated.
• the animals were clinically examined with a slit lamp from day 9 after immunization with S-Ag until the time of euthanasia. Histopathology of the eyes was performed and immunostaining was done on cryostat sections. The inguinal lymph nodes were removed for cytokine analysis by RT-PC.
• Tresperimus In a second experiment, one group of rats received three injections of Tresperimus in vitreous and the control rats were injected with saline. Rats were observed clinically and subjected to delayed-type hypersensitivity (HTR) analysis. Levels of Tresperimus in plasma and ocular tissues were measured 1, 3 and 8 days after the third injection.
• HTR delayed-type hypersensitivity
• the animals were examined with a slit lamp on day 7, and then daily from day 11 until the time of euthanasia to assess the onset of the disease and the severity of the disease.
• the intensity of clinical ocular inflammation was scored on a scale of 0 to 7 for each eye as previously described (Kozak, Eur. J. Imm. 2004). 2. Histopathology
• the eyes of enucleated rats were fixed, treated, paraffin sections were made and stained with hematoxylin-eosin-saffron for histological evaluation.
• the sections were examined and scored according to the severity of the KAU on a semi-quantitative scale of 0 to 7 as follows; (0) no tissue destruction, (1-2) destruction of external segments of rods and cones, (3-4) destruction of the outer nuclear layer, (5-6) destruction of the inner nuclear layer, and (7) ) destruction of the ganglion cell layer.
• a primary antibody against NOS-2 (Beckton Dickinson Biosciences, Transduction Laboratories, San Jose, USA), a primary antibody against NF-KBp65, and a secondary antibody conjugated to Alexa Fluor® 488 (Molecular Probes, Eugene, OR) was used.
• a macrosialin anti-CD68 primary antibody (EDI clone) (Serotec, Oxford, UK) followed by a Alexa 564 conjugated secondary antibody (red).
• the sections were observed by fluorescence photomicroscopy (FXA, Microphot, Nikon, Melville, NY) and digitized micrographs were obtained with a digital camera (Spot, BFI Optilas, Evry, France).
• HTR was estimated by an atrial test measuring the specific anti-S-Ag response 18 days after immunization. Rats were sensitized with 10 ⁇ g S-Ag in the right ear and saline in the left ear. Specific atrial swelling was measured at 24 and 48 h after sensitization and the difference in thickness (mm) between the two ears was calculated.
• Tresperimus After intravitreal injection of Tresperimus, the plasma levels of the tested sample were quantified only at the first time point 1 h after the injection, with low mean concentrations close to 0.1 ⁇ (approximately 40 ng / mL). Eye tissues have were highly exposed to Tresperimus, with significant levels (> 10 ⁇ ) in the retina / choroid 8 days after injection,
• Tresperimus led to a significant reduction in the clinical severity of UAE from day 13 after immunization, compared with rats that received saline injections (day 13; * p ⁇ 0). , 02, days 14-19, *** p ⁇ 0.0006), or compared with rats that received no intraocular treatment Court 12; * p ⁇ 0.02; day 19: *** p ⁇ 0.0006) ( Figure 1).
• the severity of the disease was significantly reduced by treatment until 19 days after immunization, indicating that intraocular therapy is very effective.
• Tresperimus protects the retina against destruction and modulates the activity of macrophages
• NF-kappaBp65 nuclear and cytoplasmic expression of NF-kappaBp65, mainly in the vitreous body where many infiltrations by inflammatory cells occur. are visible.
• rats treated with Tresperimus low infiltration by inflammatory cells is visible in ocular tissues, with a reduced number of infiltrating cells in the tissues and ocular media and showing only cytoplasmic expression of NF-kappaBp65.
• T-PC Cytokines in the inguinal lymph nodes
• Tresperimus In conclusion, the injection of Tresperimus into the posterior pole of the rat eye at the level of the posterior zone of the body allowed it to diffuse into the anterior and posterior segments of the eye, as demonstrated by its efficacy on anterior and posterior ocular inflammation in UAE. In addition, low levels ( ⁇ 90 ng / mL) of Tresperimus were found in the plasma with no effect on response. systemic immune system. In fact, the effect of Tresperimus was limited to the eye, confirming that no effective diffusion into the general circulation occurred.
• Tresperimus performed after immunization with S-Ag during the afferent phase of the disease (days 6, 9, 12) are effective in reducing clinical ocular inflammation and retinal retinal photoreceptors.
• HTR delayed-type hypersensitivity
• ocular treatment has no effect on the systemic immune response. Indeed, in the inguinal lymph nodes draining the immunization site, the level of inflammatory cytokines like TNF-alpha, and cytokines produced by T lymphocytes like IL-2, IFN-gamma (interferon-gamma), IL-17 was not modified by treatment with Tresperimus.
• the endotoxin-induced uveitis model is a model of acute eye inflammation in rats or mice, induced by systemic or local injection of lipopolysaccharide (LPS) gram-negative bacteria. It is a model for acute human anterior uveitis that is often associated with systemic disorders, such as Crohn's disease, ankylosing spondylathitis, and Blau's syndrome.
• LPS lipopolysaccharide
• UIE is characterized by rupture of the blood-eye barrier, intraocular infiltration by inflammatory cells into the anterior and posterior segments of the eye, and by the production of inflammatory cells, NO, cytokines and inflammatory chemokines. infiltrated mainly macrophages, polymorphonuclear leukocytes (PMNs) and ocular cells of the vascular endothelium, retinal pigment epithelium, microglia and Miiller cells. Although this inflammatory uveitis is spontaneously resolving in a few days involving the innate immune system, it is responsible for significant lesions of ocular tissues.
• PMNs polymorphonuclear leukocytes
• mice Female eight week old Lewis rats (R. Janvier, Le Genest Saint Isie, France) weighing about 250 g were used in this study and received an injection, in the pad of one of their paws, of 200 ⁇ g of Salmonella LPS. typhimurium (Sigma) in 0.1 ml of sterile water.
• Tresperimus was administered by drops instillation of 5% (w / w) and 0.5% (w / w) in a 0.1% (w / w) aqueous solution of sodium hyaluronate, twice daily. in each eye and for 4 days.
• the 3rd day LPS was administered in the bearing of a leg and 24 hours later the Tres Cyprusmus was administered one last time. The animals were then examined with a slit lamp, their blood was collected and then sacrificed. The eyes were then taken for analysis.
• Tresperimus was evaluated in the UIE model in rats. Acute and bilateral ocular inflammation induced by LPS injection is characterized by infiltration of inflammatory cells 4 hours after injection. It is maximum between 18 and 24 hours and disappears after 4 days.
• Tresperimus was instilled twice daily for 4 days at 5% (w / w) and 0.5% (w / w) in a 0.1% aqueous solution of sodium hyaluronate.
• the results are expressed in clinical scores ⁇ SEM for each eye.
• Glarative tears are essentially palliative and aim to replace or preserve the tears of a subject by the frequent application of artificial tears. Severe dry eye disease, characterized by severe corneal injury with increased risk of secondary infections, may be treated occasionally with anti-inflammatory therapy.
• Tresperimus was studied in a dry eye mouse model using pharmacological inhibition of tear production that induces epithelial changes in the ocular surface resembling human KCS, and which are exacerbated by desiccating environmental stress. .
• Eye dryness is induced in mice by the combination of Scopolamine, which blocks muscarinic cholinergic receptors of the lacrimal glands and by placing mice in a blower hood that reduces moisture and increases airflow.
• Scopolamine which blocks muscarinic cholinergic receptors of the lacrimal glands and by placing mice in a blower hood that reduces moisture and increases airflow.
• the production and volume of watery tears, the clearance of tears and the function of the corneal barrier are evaluated before treatment and twice weekly after treatment. The results are compared between groups of untreated control mice and groups of mice placed in the blower hood and treated with the anticholinergic agent Scopolamine treated or not treated with Tresperimus.
• mice Male 129SV / CD-1 mice were used in this study and received three subcutaneous injections of 200 ⁇ scopolamine 2.5 mg / ml in saline for 21 days. The mice were placed in a blower hood (humidity ⁇ 50%) for the duration of the experiment.
• the Lacrimal Film Stability Test (TBUT) is used to evaluate the degree of dry eye by measuring the time elapsed between a complete blink of the eye and the development of a first sign of dry stain on the tear film.
• the volume of tears was measured for three weeks in C57B16 mice using the phenol red test.
• the results reported in FIG. 7 are expressed as the mean volume of tears (in millimeters) ⁇ the standard deviation of the mean (SEM). They show that the volume of tears decreased dramatically two days after the start of subcutaneous injections of Scopolamine.
• Figure 8 shows that Scopolamine treatment and dry air exposure led to a decrease in tear film stability as measured by the tear film tear time test with a significant decrease over the first 3 days then a gradual decrease until 21 days.
• Dexamethasone only showed a modest effect which did not continue on day 21.
• Corticosteroids show a regression of macular edema and neovascularization.
• adverse effects are common (ocular hypertension, cataracts, endophthalmitis) and, in addition, the long-term efficacy in diabetic macular edema has not been proven compared to laser treatment.
• Tresperimus was evaluated in rats on a commonly described model of diabetic retinopathy, the Streptozotocin-induced Type I Diabetes Model.
• This rat model mimics human disease by inducing hyperglycemia related to the destruction of pancreatic beta cells, cells that normally regulate blood glucose by producing a hormone, insulin.
• pancreatic beta cells cells that normally regulate blood glucose by producing a hormone, insulin.
• vasculopathy does not progress to neovascularization as seen in humans.
• Streptozotocin is administered by intravenous injection to fasting rats. Hyperglycemia develops rapidly within five days of treatment with streptozotocin. Three weeks after induction of diabetes, VEGF levels and biomarkers of inflammation are measured in the vitreous. The electroretinogram (ERG) measurements of the a and b waves and oscillatory potentials are analyzed to control the photoreceptor lesions. The results are compared between control group of non-diabetic rats and group of diabetic rats treated with Tresperimus or a vehicle.
• ERP electroretinogram
• Diabetes was induced in Sprague Dawley rats (SD) rats (200 g) after overnight fasting with a single intravenous injection of 60 mg / kg streptozotocin (Sigma) in sodium citrate buffer, pH 4.5.
• Non-diabetic control animals received citrate buffer only. Five days later, animals with a blood glucose level above 5 g / 1 were considered diabetic.
• Electroretinography ECG
• the diabetic rats were acclimated to darkness overnight before the ERG examination using an LKC electroretinograph. A series of responses based on dark intensity was recorded using a series of field flash (Ganzfeld) to obtain a retinal response via the rods. The amplitude and latency of the individual ripple components of the ERG (waves a and b, pseudo-oscillations), as well as the oscillatory potentials were measured in a conventional manner.
• Tresperimus The effect of Tresperimus was evaluated in the experimental model of streptozotocin-induced diabetic retinopathy in SD rats. Streptozotocin destroyed beta cells in the pancreas and induced hyperglycemia, mimicking type 1 diabetes. The retina of diabetic animals showed biochemical and electrophysiological abnormalities correlated with inflammation.
• FIG. 10 shows that after two weeks of treatment with twice-daily administrations of 0.2% Tepherimus ocular instillation, Tresperimus significantly improved the amplitude of the pseudo-oscillations compared to the control group (treated diabetic rats). by the vehicle) and also improved the amplitudes of the waves a and b and oscillatory potentials, suggesting a neuroprotective effect of retinal functions and in particular cones and rods in diabetic rats.

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