WO1998015238A1 - Device for stretching the crystalline capsule, capable of being charged with at least one active principle and for releasing said active principle, and its preparation - Google Patents

Device for stretching the crystalline capsule, capable of being charged with at least one active principle and for releasing said active principle, and its preparation Download PDF

Info

Publication number
WO1998015238A1
WO1998015238A1 PCT/FR1997/001785 FR9701785W WO9815238A1 WO 1998015238 A1 WO1998015238 A1 WO 1998015238A1 FR 9701785 W FR9701785 W FR 9701785W WO 9815238 A1 WO9815238 A1 WO 9815238A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogel
tensioning
charged
bioresorbable
capsule according
Prior art date
Application number
PCT/FR1997/001785
Other languages
French (fr)
Inventor
Joseph Colin
Rémi BOUGARAN
Franck Villain
Original Assignee
Corneal Industrie
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 Corneal Industrie filed Critical Corneal Industrie
Priority to EP97944934A priority Critical patent/EP0946125A1/en
Publication of WO1998015238A1 publication Critical patent/WO1998015238A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/14—Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/14—Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
    • A61F2/16—Intraocular lenses
    • A61F2/1694—Capsular bag spreaders therefor
    • 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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/14—Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
    • A61F2/16—Intraocular lenses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea

Definitions

  • Device for tensioning the crystalline capsule capable of being loaded with at least one active principle and of releasing said active principle, and its preparation.
  • the subject of the present invention is a device for tensioning the lens capsule, capable of being loaded with at least one active principle and of progressively releasing said active principle.
  • Said device is perfectly bi-functional. After its implantation, charged, in the emptied capsular bag of the lens, it is able on the one hand, for many years, to avoid the retraction of said emptied bag and on the other hand, for a certain duration, to release gradually, at least one active ingredient. This release does not jeopardize his integrity. It does not bring into play the bioresorbable nature of all or even part of its structure.
  • the shrinkage of the capsular bag is a relatively common complication associated with cataract surgery.
  • a device for tensioning said bag generally a ring, made of polymethyl methacrylate (PMMA).
  • PMMA polymethyl methacrylate
  • surgeons have already demonstrated the beneficial effects of this type of device and several companies, including the companies Morcher and Cornéal market models.
  • the main function of this device is as stated above to maintain the volume of the capsule emptied of the lens.
  • a device of this type can also be requested for positioning and maintaining the intraocular lens (EP-A-0 507 292 and EP-A-0 478 929).
  • the Applicant has developed an effective device, overcoming both the mechanical and biological complications of cataract surgery, that is to say, ensuring both the almost permanent tensioning of the lens capsule and the gradual release of at least one active ingredient.
  • the specifications of such a device provided that it has adequate mechanical properties (in particular of rigidity) to exert sufficient force on the emptied bag, in order to avoid its retraction and that it can however be hydrated to be charged in principle (s) active (s); while presenting a simple structure, in one piece.
  • the process of providing a satisfactory solution to such specifications was by no means obvious. Said satisfactory solution constitutes the subject of the invention currently claimed.
  • the Applicant has therefore developed a device for tensioning the lens capsule, capable of being loaded with at least one active principle and of progressively releasing said active principle, of a new type.
  • Said device typically, is a single piece, not bioresorbable (it is thus capable of ensuring the tensioning of the bag for many years) and all or part of its mass consists of at least one volume of hydrogel capable to be charged in principle (s) active (s); said hydrogel volume having at least one surface for exchange with the outside (exchange surface, through which the active principle (s) is (are) capable of) to be released).
  • the release of active principle (s) does not imply the bioresorbable nature of the charged material involved.
  • the integrity of the device is preserved.
  • the release of the active ingredient does not affect the mechanical properties of said device.
  • the device of the invention is therefore original in that in its one-piece, non-absorbable structure, rigid enough to provide the required tension on the empty bag, it includes a hydrogel (a hydrophilic structure) capable of being charged in principle (s ) active.
  • - uncharged the hydrogel (s) constituting its structure or entering its structure having not been charged with at least one active principle.
  • Said uncharged device can be implanted in the state or kept, in the state, in anticipation of a future loading and of an implantation, charged;
  • - loaded the hydrogel (s) constituting its structure or entering its structure including at least one active principle (with a view to its subsequent release, after the implantation of said device in the crystalline cavity). Its two forms form an integral part of the present invention.
  • the device of the invention - loaded or unloaded - exists according to two main variants, which are not exhaustive.
  • the entire mass of said device is made of non-bioresorbable hydrogel.
  • a single hydrogel, not bioresorbable, capable of being charged in principle (s) active (s) and giving the device the required mechanical properties constitutes the entire mass of said device.
  • Such a device is directly cut from a block of such a hydrogel.
  • the one-piece mass of the device consists of at least two hydrogels, of different nature, chemically linked. We may thus wish to bring and deliver to the lens capsule at least two active ingredients which are not very compatible.
  • Such a device can also be cut from a block made up of different hydrogels.
  • the entire mass of the device of the invention which is not in hydrogel is not capable of being charged in principle (s) active (s).
  • Part of said mass is made of a non-bioresorbable hydrophobic material. Such material cannot be loaded in active principle (s). Its presence may be appropriate to strengthen the structure of the device of the invention, to strengthen its mechanical properties.
  • the arrangement of the part (or even parts) of hydrogel, capable of being charged (s) in active principle (s) and of the part (or even of the parts) of hydrophobic material (s) is obviously such that the said active principle (s) can be released.
  • the volume (s) of hydrogel capable of being charged has at least one surface for exchange with the outside.
  • the devices of the invention in accordance with this second variant - part of their mass is made of a hydrophobic material - also have a one-piece structure.
  • the hydrophobic (s) and hydrophilic (s) (hydrogel (s)) materials entering into their structure are linked chemically, not mechanically. (In any event, whatever the variant embodiment of the devices of the invention, their structure does not include an attachment).
  • a hydrophilic, crosslinked, advantageously acrylic copolymer is recommended.
  • Said copolymer is obtained from at least one hydrophobic monomer advantageously acrylic and from at least one hydrophilic monomer advantageously acrylic.
  • the hydrophilic monomer gives said copolymer its hydrophilic properties while the hydrophobic monomer gives it a certain mechanical resistance.
  • Such copolymers must be crosslinked so that the device has the required mechanical properties.
  • hydrogel a crosslinked copolymer obtained from a mixture of at least one hydrophobic monomer chosen from methacrylates or alkyl acrylates (alkyl, generally C ⁇ -C ⁇ ), advantageously methacrylates C 1 -C 2 alkyl and at least one hydrophilic monomer chosen from hydroxyalkyl methacrylates or acrylates (hydroxyalkyl, generally C 2 -C 8 ), advantageously hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxybutyl methacrylate (HBMA), hydroxyhexyl methacrylate (HHMA).
  • hydrophobic monomer chosen from methacrylates or alkyl acrylates (alkyl, generally C ⁇ -C ⁇ )
  • methacrylates C 1 -C 2 alkyl advantageously methacrylates C 1 -C 2 alkyl
  • hydrophilic monomer chosen from hydroxyalkyl methacrylates or acrylates (hydroxyalkyl, generally C 2 -
  • MMA methyl methacrylate
  • EMA ethyl methacrylate
  • PMA -propyl methacrylate
  • BMA, n-BMA butyl methacrylate
  • HMA, n-HMA -hexyl methacrylate
  • DMA n-dodecyl methacrylate
  • hydrophilic (non-acrylic) monomers can also be used to prepare hydrogels suitable for the purposes of the invention.
  • N-vinyl pyrrolidone and acrylamide are examples of suitable crosslinkers.
  • Crosslinking is obtained by the conventional intervention of a crosslinking agent during the implementation of the copolymerization reaction.
  • suitable crosslinkers there may be mentioned, in a nonlimiting manner, ethylene glycol dimethacrylate, dibutanediol dimethacrylate and hexanediol dimethacrylate. Crosslinking is generally carried out in the absence of oxygen. It is then easier to control it and we obtain purer products.
  • Crosslinked copolymers obtained from mixtures of monomers: C 1 -C 2 alkyl methacrylate / hydroxyethyl methacrylate (HEMA) C 1 -C 12 alkyl methacrylate / hydroxypropyl methacrylate (HPMA) are particularly preferred.
  • HEMA hydroxyethyl methacrylate
  • HPMA hydroxypropyl methacrylate
  • the hydrophobic monomer retained may consist of methyl methacrylate (MMA), the polymer of which is to date the only material used for the manufacture of devices for tensioning the crystalline capsule.
  • MMA methyl methacrylate
  • said polymer could have been modified” to gain hydrophilicity - and thus be able to charge and gradually release active ingredients in the eye - without losing too much in mechanical properties.
  • a person skilled in the art is capable of developing a hydrogel, from which can be cut a device for tensioning the suitable crystalline capsule.
  • the least hydrophilic hydrogels release, once charged, their charge in active principle (s) over a longer period.
  • Said less hydrophilic hydrogels are, however, those which can hardly be charged in active principle (s).
  • a person skilled in the art will know how to adapt the characteristics of the hydrogel to the nature of the active ingredient (s) involved in order to optimize the release thereof (these).
  • the thickness of the devices of the invention can be greater than that of devices of the same type of the prior art. Said thickness obviously remains compatible with their introduction into the emptied bag. It is in fact advisable on the one hand to be able to implant said devices and on the other hand that these, once implanted, exert on the walls of the crystalline cavity a sufficient tension force ... but not excessive.
  • hydrogels whose nature has been specified above are suitable for representing 100% of the mass of the devices of the invention. They are obviously suitable for representing only part of said mass.
  • the loading in principle (s) active (s) of the hydrogel (hydrogels) intervening (S) in the mass of the devices of the invention does not raise any particular difficulty. This is explained below in the presentation of a process for developing loaded devices of the invention.
  • the volume (s) of hydrogel charged once the device of the invention placed in the crystalline cavity, will (will) release its (their) charge (s) ) of active principle (s) through the exchange surface (s) that it (s) present (s) with the outside. It may be desirable to intervene to modify (slow down) the kinetics of this exchange, of this release of active principle (s) (release which, in any event, is called to take place gradually, by broadcast).
  • This technique of surface coating, to optimize a gradual controlled release of active ingredient is per se a known technique.
  • two routes have more particularly been developed for generating a coating.
  • a first route consisted in absorbing on the surface of a device of the invention a reaction mixture of acrylics, then in polymerizing this mixture. By interpenetration of the polymer networks, a more hydrophobic membrane capable of slowing the release of the active principle (s) is thus created on the surface of the volume (s) of hydrogel.
  • the second route consisted in depositing on said surface of a device of the invention a bioresorbable polymer or copolymer. Such (co) polymers are perfectly known to those skilled in the art.
  • Such poly- ⁇ -hydroxy acids are used in particular in the biomedical field, for, for example, the manufacture of osteosynthesis plates or bioresorbable sutures. It is judicious to choose as precursor of such a bioresorbable coating products soluble in solvents, in particular organic such as tetrahydrofuran and dioxane, in which the active active ingredients are insoluble.
  • the devices of the invention, loaded with active principle (s) are then simply immersed in a relatively concentrated polymer solution, then removed.
  • the charged devices of the invention may comprise on at least part (generally all) of their exchange surface: volume (s) of hydrogel (s) charged (s) / exterior, a surface coating, intended to slow the release of the active ingredient (s) present in the said volume (s) of hydrogel. It has also been noted that such a coating generally also affects the regularity of said release.
  • a coating advantageously consists of a layer or membrane of a more hydrophobic polymer than the hydrogel which it covers (see the first route presented above) or of a bioresorbable polymer (see the second route presented above, preferred ).
  • the devices for tensioning the lens capsule according to the invention are original in that a non-bioresorbable hydrogel capable of being charged with active principle (s) enters their non-biodegradable one-piece structure, or even constitutes said structure.
  • s active principle
  • they hardly present originality in terms of their geometry.
  • they may have a cross section greater than that of the devices known from the prior art. They may also not have a uniform profile over their entire length. To gain flexibility, they can present a refined profile in at least one zone.
  • they have overall shapes quite similar to those of said known devices and said shapes are suitably sized, relative to the dimensions of the eye so that the desired tensioning effect is ensured.
  • They can in particular be in the form of open rings, of substantially circular or polygonal section with broken angles; they can also be in the form of a piece of propeller (the pitch of which is substantial), the cross section of which can also be substantially circular or polygonal with broken angles. They can also have the shape of a toothed wheel, of any section ...
  • the device for tensioning the crystalline capsule consists of a ring open of substantially circular section or polygonal with broken angles, in hydroxyethyl methacrylate / methyl methacrylate (HEMA / MMA) or hydroxypropyl methacrylate / methyl methacrylate (HPMA / MMA), charged with at least one active principle and coated on its entire external surface d '' a bioresorbable layer of a copolymer of ⁇ -hydroxy acids.
  • HEMA / MMA hydroxyethyl methacrylate / methyl methacrylate
  • HPMA / MMA hydroxypropyl methacrylate / methyl methacrylate
  • the device of the invention is therefore advantageous in that it is capable of effectively ensuring the tensioning of the crystalline capsule, for many years (up to 20 years and more ) while having, following its implantation, progressively delivered into said capsule at least one active principle.
  • Said active ingredient is introduced and gradually released, in an original manner, via the volume (s) of charged hydrogel (s) constituting all or part of the mass of said device. Such a gradual release advantageously replaces repeated injections ...
  • the devices of the invention In view of the biological complications associated with cataract surgery, recalled above, it is recommended to use the devices of the invention to gradually release at least one antibiotic and / or at least one antimitotic and / or at least one inducer of terminal cell differentiation.
  • the hydrogel acting as a constituent of its mass close (s) separately or in combination, at least one antibiotic and / or at least one antimitotic and / or at least one cell differentiation inducer.
  • the devices of the invention of which at least one hydrogel capable of being charged constitutes all or part of the mass, can obviously contain said charged hydrogel, in a more or less hydrated state, before their implantation. It is strongly recommended to install said loaded devices in the dry state.
  • the advantage of installing such a dry device is obviously that the release kinetics of the active principle (s) is further limited by the rate of hydration of the material containing them.
  • the deposition of a coating intended to slow the release of the said active principle (s) charged (s), on its surface, to obtain a charged device.
  • the size of the device of the invention in such a block does not raise any particular difficulty.
  • Said size is generally followed by a polishing, intended to eliminate any roughness, any sharp angle of the cut shape.
  • Said cut and generally polished shape is then cleaned.
  • the aim is to purify it, to extract from it any polymerization residue, the release of which into the eye (in particular during hydration of the hydrogel, which is advantageously introduced dry) would be harmful. .
  • a form is obtained which it is possible to implant, advantageously hydrated, uncharged, for the tensioning of the lens capsule. If it is desired to load said form, it is advantageous to dry it beforehand, generally by heating under vacuum.
  • the device of the invention which is not loaded is obtained which can be kept in the state for subsequent implantation after loading or which can be loaded immediately.
  • said dry form is immersed in a solution containing the said active principle (s).
  • a person skilled in the art perfectly masters such a step of loading a hydrogel.
  • the charged device is extracted from the charging solution and can be used, implanted, as is.
  • the method of the invention therefore comprises, at this level, advantageously a step of drying the loaded device.
  • said method of the invention comprises an additional step intended to generate a coating on the surface of the charged device obtained.
  • Techniques for depositing such a coating have been discussed upstream in the present text. They are in themselves perfectly known to those skilled in the art.
  • Figure 1 is a plan view of a device for tensioning the lens capsule, according to the invention.
  • Figure 2 is a section, taken along V-V of said figure 1.
  • Figures 3 to 6 are sections, taken along V - V of plan views, similar to Figure 1, of other tensioning devices of the lens capsule according to the invention.
  • the devices shown in said Figures 1 to 6, and in particular the device (1) of Figures 1 and 2, are open rings of polygonal section with broken angles.
  • the device (1) according to Figures 1 and 2 has a one-piece structure in a hydrogel H, not bioresorbable, charged with an active principle (2).
  • the active ingredient (2) is shown diagrammatically, which in fact is dispersed in the said hydrogel H.
  • the entire external surface of said device (1) constitutes the exchange surface by which the active principle (2) is capable of being released.
  • the devices of the invention according to FIGS. 3 to 6 typically have a part of their mass, having at least one surface for exchange with the outside, in a hydrogel H, not bioresorbable, charged with active principle ( 2) and the complementary part made of a non-bioresorbable hydrophobic material: M.
  • Said hydrogels H and non-bioresorbable hydrophobic materials M of the different devices shown can be identical or different. Within of the same device, for example those according to FIGS. 4 to 6, it is in particular possible to involve two hydrophobic non-bioresorbable materials M.
  • a device of the invention has been developed and tested as specified below.
  • the material obtained is extracted in a methanol / water mixture: 50/50 by volume. This removes the residue from the polymerization.
  • the mass of extractables was found to be 3.7%.
  • the water content of the hydrated hydrogel prepared is 15.5% by mass.
  • the dry implant is placed in a bottle containing 5 ml of physiological saline, this volume corresponding to the average volume of one eye.
  • the solution is regularly replaced and the 5-FU is dosed in the solution thus recovered.
  • the time required for full release of the loaded 5-FU is 9 days. Only

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention concerns a device for stretching the crystalline capsule (1), capable of being charged with at least one active principle and for gradually releasing said active principle. The invention is characterised in that a volume of biologically non- absorbable hydrogel, capable of being charged with active principle(s), constitutes the whole or part of the biologically non-absorbable single-piece mass of said device (1), having at least one externally exchange surface. The invention also concerns a method for preparing such a device.

Description

Dispositif de mise en tension de la capsule cristallinienne, susceptible d'être chargé en au moins un principe actif et de libérer ledit principe actif, et sa préparation.Device for tensioning the crystalline capsule, capable of being loaded with at least one active principle and of releasing said active principle, and its preparation.
La présente invention a pour objet un dispositif de mise en tension de la capsule cristallinienne, susceptible d'être chargé en au moins un principe actif et de libérer progressivement ledit principe actif. Ledit dispositif est parfaitement bi- fonctionnel. Après son implantation, chargé, dans le sac capsulaire vidé du cristallin, il est capable d'une part, pendant de nombreuses années, d'éviter la rétraction dudit sac vidé et d'autre part, pendant une certaine durée, de libérer, de façon progressive, au moins un principe actif. Cette libération ne met pas en cause son intégrité. Elle ne met pas en jeu le caractère biorésorbable de la totalité voire d'une partie de sa structure.The subject of the present invention is a device for tensioning the lens capsule, capable of being loaded with at least one active principle and of progressively releasing said active principle. Said device is perfectly bi-functional. After its implantation, charged, in the emptied capsular bag of the lens, it is able on the one hand, for many years, to avoid the retraction of said emptied bag and on the other hand, for a certain duration, to release gradually, at least one active ingredient. This release does not jeopardize his integrity. It does not bring into play the bioresorbable nature of all or even part of its structure.
La rétraction du sac capsulaire est une complication relativement fréquente associée à la chirurgie de la cataracte. Il a été proposé, pour pallier ce problème, d'introduire, avant la mise en place d'une lentille intraoculaire, un dispositif de tension dudit sac, généralement un anneau, en polyméthacrylate de méthyle (PMMA). Plusieurs chirurgiens ont déjà démontré les effets bénéfiques de ce type de dispositif et plusieurs sociétés, dont les sociétés Morcher et Cornéal en commercialisent des modèles. La fonction principale de ce dispositif est comme précisé ci-dessus de maintenir le volume de la capsule vidée du cristallin. Un dispositif de ce type peut par ailleurs être sollicité pour le positionnement et le maintien de la lentille intraoculaire (EP-A-0 507 292 et EP-A-0 478 929).On a suggéré également, notamment dans ladite demande EP-A-0 507 292, que la seule présence d'un tel dispositif à l'équateur de la capsule, empêcherait la prolifération des cellules cristalliniennes restantes. Ce problème de la prolifération des cellules restantes est un réel problème, comme cela est explicité ci-après.The shrinkage of the capsular bag is a relatively common complication associated with cataract surgery. To overcome this problem, it has been proposed to introduce, before the insertion of an intraocular lens, a device for tensioning said bag, generally a ring, made of polymethyl methacrylate (PMMA). Several surgeons have already demonstrated the beneficial effects of this type of device and several companies, including the companies Morcher and Cornéal market models. The main function of this device is as stated above to maintain the volume of the capsule emptied of the lens. A device of this type can also be requested for positioning and maintaining the intraocular lens (EP-A-0 507 292 and EP-A-0 478 929). It has also been suggested, in particular in said application EP-A -0 507 292, that the mere presence of such a device at the equator of the capsule, would prevent the proliferation of the remaining crystalline cells. This problem of the proliferation of the remaining cells is a real problem, as explained below.
En effet, en sus des complications "mécaniques" de la chirurgie de la cataracte rappelées ci-dessus, ladite chirurgie est perturbée par des complications biologiques telles, notamment, la cataracte secondaire et l'endophtalmie. L'endophtalmie, complication dramatique pouvant aboutir à la perte de l'oeil, est provoquée par l'insertion de bactéries à l'intérieur de l'oeil, au cours de la chirurgie. L'endophtalmie est traitée par chimiothérapie, par injections intraoculaires d'antibiotiques. Les antibiotiques les plus couramment utilisés sont la gentamycine ou la vancomycine. En référence à la cataracte secondaire, on peut préciser ce qui suit.In fact, in addition to the "mechanical" complications of cataract surgery mentioned above, said surgery is disturbed by biological complications such as, in particular, secondary cataract and endophthalmitis. Endophthalmitis, a dramatic complication that can lead to the loss of the eye, is caused by the insertion of bacteria inside the eye during surgery. Endophthalmitis is treated by chemotherapy, by intraocular injections of antibiotics. The most commonly used antibiotics are gentamycin or vancomycin. With reference to secondary cataract, the following can be clarified.
Lorsqu'il vide le sac capsulaire, le chirurgien essaie d'enlever la totalité des cellules cristalliniennes, de parfaitement nettoyer la capsule. Il reste toujours, malheureusement, quelques unes de ces cellules qui peuvent proliférer et provoquer alors une opacification secondaire de la capsule postérieure ou cataracte secondaire. Cette opacification est aujourd'hui traitée au laser, en pratiquant une ouverture dans ladite capsule postérieure. Une telle ouverture est responsable , dans un nombre relativement important de cas, de complications plus sévères, telles, par exemple, des décollements de rétine. Il n'est pas proposé, à ce jour, de traitements médicamenteux de cette opacification secondaire. Des pistes existent cependant. On sait que des antimitotiques, comme le 5-fluorouracil, permettent de limiter la prolifération des cellules. Toutefois, la rapide élimination de telles drogues imposeraient des injections répétées, contraignantes pour le chirurgien et le patient, susceptibles d'entraîner des problèmes de toxicité. D'autres voies sont envisageables comme, par exemple, l'utilisation de molécules induisant l'apoptose des cellules. Mais dans un tel contexte, on serait également confronté au problème de la rapide élimination de ces drogues qui imposerait, de la même façon, des injections répétées... On pourrait aussi envisager de formuler et d'utiliser ce type de médicaments efficaces sous la forme de collyres. Toutefois, l'utilisation de tels collyres se révélerait probablement dangereuse, vu la toxicité cornéenne et extraoculaire desdits médicaments. A ce jour, on ne propose donc pas de solution satisfaisante pour prévenir les complications biologiques - endophtalmie et cataracte secondaire - de la chirurgie de la cataracte. Une telle solution satisfaisante semble devoir se baser sur l'intervention d'un système à libération contrôlée de principe(s) actif(s).When emptying the capsular bag, the surgeon tries to remove all of the lens cells, to perfectly clean the capsule. Unfortunately, there are still some of these cells which can proliferate and then cause secondary clouding of the posterior capsule or secondary cataract. This opacification is now treated with a laser, by making an opening in said posterior capsule. Such an opening is responsible, in a relatively large number of cases, for more severe complications, such as, for example, retinal detachments. To date, no drug treatments have been proposed for this secondary clouding. Tracks do exist, however. It is known that antimitotics, such as 5-fluorouracil, make it possible to limit the proliferation of cells. However, the rapid elimination of such drugs would impose repeated injections, binding on the surgeon and the patient, which could lead to toxicity problems. Other ways are possible such as, for example, the use of molecules inducing cell apoptosis. But in such a context, we would also be faced with the problem of the rapid elimination of these drugs which would, in the same way, require repeated injections ... We could also consider formulating and using this type of effective drugs under the form of eye drops. However, the use of such eye drops would probably prove dangerous, given the corneal and extraocular toxicity of said drugs. To date, therefore, no satisfactory solution has been proposed for preventing the biological complications - endophthalmitis and secondary cataract - of cataract surgery. Such a satisfactory solution seems to have to be based on the intervention of a controlled release system of active principle (s).
De tels systèmes à libération contrôlée ont notamment été décrits dans la demande EP-A- 0 544 948. Il s'agit d'implants dont la structure pleine libère un principe actif par biodégradabilité ou dont la structure creuse libère un principe actif par diffusion au travers d'une paroi. De tels implants ne sauraient présenter les propriétés mécaniques requises pour assurer la mise en tension de la capsule cristallinienne. L'implant décrit dans la demande EP-A-0 478 929, plus particulièrement prévu pour le positionnement d'une lentille intraoculaire à l'intérieur du sac capsulaire, présente, lui, sur sa face externe, une gorge, dans laquelle peut être insérée une éponge chargée en principe actif. Une telle construction qui fait intervenir pour la libération d'un principe actif une pièce rapportée ne parait guère satisfaisante. Dans ce contexte, la Demanderesse a développé un dispositif efficace, palliant à la fois les complications mécaniques et biologiques de la chirurgie de la cataracte, c'est-à-dire, assurant à la fois la mise en tension quasi permanente de la capsule cristallinienne et la libération progressive d'au moins un principe actif. Le cahier des charges d'un tel dispositif prévoyait qu'il présente des propriétés mécaniques adéquates (notamment de rigidité) pour exercer une force suffisante sur le sac vidé, afin d'éviter sa rétraction et qu'il puisse cependant s'hydrater pour être chargé en principe(s) actif(s); tout en présentant une structure simple, d'une seule pièce. La démarche pour apporter une solution satisfaisante à un tel cahier des charges n'a été nullement évidente. Ladite solution satisfaisante constitue l'objet de l'invention présentement revendiquée.Such controlled release systems have in particular been described in application EP-A-0 544 948. They are implants whose solid structure releases an active principle by biodegradability or whose hollow structure releases an active principle by diffusion to the across a wall. Such implants cannot have the mechanical properties required to ensure the tensioning of the lens capsule. The implant described in patent application EP-A-0 478 929, more particularly intended for positioning an intraocular lens inside the capsular bag, has, on its external face, a groove, in which can be inserted a sponge loaded with active ingredient. Such a construction which involves an added part for the release of an active principle does not seem satisfactory. In this context, the Applicant has developed an effective device, overcoming both the mechanical and biological complications of cataract surgery, that is to say, ensuring both the almost permanent tensioning of the lens capsule and the gradual release of at least one active ingredient. The specifications of such a device provided that it has adequate mechanical properties (in particular of rigidity) to exert sufficient force on the emptied bag, in order to avoid its retraction and that it can however be hydrated to be charged in principle (s) active (s); while presenting a simple structure, in one piece. The process of providing a satisfactory solution to such specifications was by no means obvious. Said satisfactory solution constitutes the subject of the invention currently claimed.
La Demanderesse a donc mis au point un dispositif de mise en tension de la capsule cristallinienne, susceptible d'être chargé en au moins un principe actif et de libérer progressivement ledit principe actif, d'un type nouveau. Ledit dispositif, de façon caractéristique, est monobloc, non biorésorbable (il est ainsi capable d'assurer la mise en tension du sac pendant de nombreuses années) et toute ou partie de sa masse est constituée d'au moins un volume d'hydrogel susceptible d'être chargé en principe(s) actif(s) ; ledit volume d'hydrogel présentant au moins une surface d'échange avec l'extérieur (surface d'échange, au travers de laquelle, le(s) principe(s) actif(s) est(sont) susceptible(s) d'être libéré(s)).The Applicant has therefore developed a device for tensioning the lens capsule, capable of being loaded with at least one active principle and of progressively releasing said active principle, of a new type. Said device, typically, is a single piece, not bioresorbable (it is thus capable of ensuring the tensioning of the bag for many years) and all or part of its mass consists of at least one volume of hydrogel capable to be charged in principle (s) active (s); said hydrogel volume having at least one surface for exchange with the outside (exchange surface, through which the active principle (s) is (are) capable of) to be released).
Dans le concept du dispositif de l'invention, la libération de principe(s) actif(s) n'implique pas le caractère biorésorbable du matériau chargé intervenant. L'intégrité du dispositif est préservé. La libération du principe actif n'affecte pas les propriétés mécaniques dudit dispositif. Le dispositif de l'invention est donc original en ce que dans sa structure monobloc, non résorbable, suffisamment rigide pour assurer la tension requise sur le sac vide, il inclut un hydrogel (une structure hydrophile) susceptible d'être chargé en principe(s) actif(s).In the concept of the device of the invention, the release of active principle (s) does not imply the bioresorbable nature of the charged material involved. The integrity of the device is preserved. The release of the active ingredient does not affect the mechanical properties of said device. The device of the invention is therefore original in that in its one-piece, non-absorbable structure, rigid enough to provide the required tension on the empty bag, it includes a hydrogel (a hydrophilic structure) capable of being charged in principle (s ) active.
Le lecteur aura déjà compris que le dispositif de l'invention existe sous deux formes :The reader will have already understood that the device of the invention exists in two forms:
- non chargé : l'(les) hydrogel(s) constituant sa structure ou entrant dans sa structure n'ayant pas été chargé(s) en au moins un principe actif. Ledit dispositif non chargé peut être implanté en l'état ou conservé, en l'état, en prévision d'un futur chargement et d'une implantation, chargé; - chargé : l'(les) hydrogel(s) constituant sa structure ou entrant dans sa structure incluant au moins un principe actif (en vue de la libération ultérieure de celui-ci, après l'implantation dudit dispositif dans la cavité cristallinienne). Ses deux formes font partie intégrante de la présente invention. Le dispositif de l'invention - chargé ou non chargé - existe selon deux principales variantes, non exhaustives.- uncharged: the hydrogel (s) constituting its structure or entering its structure having not been charged with at least one active principle. Said uncharged device can be implanted in the state or kept, in the state, in anticipation of a future loading and of an implantation, charged; - loaded: the hydrogel (s) constituting its structure or entering its structure including at least one active principle (with a view to its subsequent release, after the implantation of said device in the crystalline cavity). Its two forms form an integral part of the present invention. The device of the invention - loaded or unloaded - exists according to two main variants, which are not exhaustive.
Selon la première, toute la masse dudit dispositif est en hydrogel non biorésorbable. Avantageusement, un unique hydrogel, non biorésorbable, susceptible d'être chargé en principe(s) actif(s) et conférant au dispositif les propriétés mécaniques requises, constitue toute la masse dudit dispositif. Un tel dispositif est directement taillé dans un bloc d'un tel hydrogel. Il n'est toutefois pas exclu du cadre de la présente invention que la masse monobloc du dispositif consiste en au moins deux hydrogels, de nature différente, liés chimiquement. On peut souhaiter ainsi apporter et délivrer dans la capsule cristallinienne au moins deux principes actifs qui ne sont pas très compatibles. Un tel dispositif peut également être taillé dans un bloc constitué de différents hydrogels.According to the first, the entire mass of said device is made of non-bioresorbable hydrogel. Advantageously, a single hydrogel, not bioresorbable, capable of being charged in principle (s) active (s) and giving the device the required mechanical properties, constitutes the entire mass of said device. Such a device is directly cut from a block of such a hydrogel. It is not however excluded from the scope of the present invention that the one-piece mass of the device consists of at least two hydrogels, of different nature, chemically linked. We may thus wish to bring and deliver to the lens capsule at least two active ingredients which are not very compatible. Such a device can also be cut from a block made up of different hydrogels.
Selon la seconde variante, toute la masse du dispositif de l'invention qui n'est pas en hydrogel n'est pas susceptible d'être chargée en principe(s) actif(s). Une partie de ladite masse est en un matériau hydrophobe non biorésorbable. Un tel matériau ne peut pas être chargé en principe(s) actif(s). Sa présence peut être opportune pour renforcer la structure du dispositif de l'invention, pour renforcer ses propriétés mécaniques. L'agencement de la partie (voire des parties) en hydrogel, susceptible d'être chargée(s) en principe(s) actif(s) et de la partie (voire des parties) en matériau(x) hydrophobe(s) est évidemment tel que le(s)dit(s) principe(s) actif(s) puisse(nt) être libéré(s). Le(les) volume(s) d'hydrogel susceptible(s) d'être chargé(s) présente(nt) au moins une surface d'échange avec l'extérieur. Par le biais d'une pluralité de volumes en hydrogel associée à au moins une partie en matériau hydrophobe, on peut également introduire des principes actifs non compatibles. Les dispositifs de l'invention, conformes à cette seconde variante - dont une partie de leur masse est en un matériau hydrophobe - présentent également une structure monobloc. Les matériaux hydrophobe(s) et hydrophile(s) (hydrogel(s)) entrant dans leur structure sont liés chimiquement, non mécaniquement. (En tout état de cause, quelle que soit la variante de réalisation des dispositifs de l'invention, leur structure n'inclut pas de pièce rapportée). Dans le cadre de cette seconde variante, on peut développer plusieurs modes de réalisation du dispositif de l'invention. Il est généralement obtenu par taille dans un bloc de matériau composite adéquat.According to the second variant, the entire mass of the device of the invention which is not in hydrogel is not capable of being charged in principle (s) active (s). Part of said mass is made of a non-bioresorbable hydrophobic material. Such material cannot be loaded in active principle (s). Its presence may be appropriate to strengthen the structure of the device of the invention, to strengthen its mechanical properties. The arrangement of the part (or even parts) of hydrogel, capable of being charged (s) in active principle (s) and of the part (or even of the parts) of hydrophobic material (s) is obviously such that the said active principle (s) can be released. The volume (s) of hydrogel capable of being charged has at least one surface for exchange with the outside. By means of a plurality of hydrogel volumes associated with at least one part made of hydrophobic material, it is also possible to introduce non-compatible active principles. The devices of the invention, in accordance with this second variant - part of their mass is made of a hydrophobic material - also have a one-piece structure. The hydrophobic (s) and hydrophilic (s) (hydrogel (s)) materials entering into their structure are linked chemically, not mechanically. (In any event, whatever the variant embodiment of the devices of the invention, their structure does not include an attachment). In the context of this second variant, it is possible to develop several embodiments of the device of the invention. It is generally obtained by size in a block of suitable composite material.
On précise ci-après la nature chimique du(des) matériau(x), susceptible(s) d'entrer dans la composition de la masse des dispositifs de l'invention.The chemical nature of the material (s), likely to enter into the composition of the mass of the devices of the invention, is specified below.
A titre d'hydrogel convenable, on préconise l'intervention d'un copolymere hydrophile réticulé avantageusement acrylique. Ledit copolymere est obtenu à partir d'au moins un monomère hydrophobe avantageusement acrylique et d'au moins un monomère hydrophile avantageusement acrylique. Le monomère hydrophile confère audit copolymere ses propriétés hydrophiles tandis que le monomère hydrophobe lui confère une certaine résistance mécanique.As a suitable hydrogel, the intervention of a hydrophilic, crosslinked, advantageously acrylic copolymer is recommended. Said copolymer is obtained from at least one hydrophobic monomer advantageously acrylic and from at least one hydrophilic monomer advantageously acrylic. The hydrophilic monomer gives said copolymer its hydrophilic properties while the hydrophobic monomer gives it a certain mechanical resistance.
De tels copolymères doivent être réticulés pour que le dispositif présente les propriétés mécaniques requises.Such copolymers must be crosslinked so that the device has the required mechanical properties.
On préconise plus particulièrement de faire intervenir comme hydrogel un copolymere réticulé obtenu à partir d'un mélange d'au moins un monomère hydrophobe choisi parmi les méthacrylates ou acrylates d'alkyle (alkyle, généralement en Cι-Cι ), avantageusement les méthacrylates d'alkyle en Cj-Ci 2 et d'au moins un monomère hydrophile choisi parmi les méthacrylates ou acrylates d'hydroxyalkyle (hydroxyalkyle, généralement en C2-C8), avantageusement le methacrylate d'hydroxyéthyle (HEMA), le methacrylate d'hydroxypropyle (HPMA), le methacrylate d'hydroxybutyle (HBMA), le methacrylate d'hydroxyhexyle (HHMA). A titre de methacrylate d'alkyle en C1-C12 (monomère hydrophobe), on préconise de faire avantageusement intervenir le methacrylate de méthyle (MMA), le methacrylate d'éthyle (EMA), le methacrylate de (n)-propyle (PMA, n-PMA), le methacrylate de (n)-butyle (BMA, n-BMA), le methacrylate de (n)-hexyle (HMA, n-HMA), le methacrylate de (n)-dodécyle (DMA, n-DMA).It is more particularly recommended to use as a hydrogel a crosslinked copolymer obtained from a mixture of at least one hydrophobic monomer chosen from methacrylates or alkyl acrylates (alkyl, generally Cι-Cι), advantageously methacrylates C 1 -C 2 alkyl and at least one hydrophilic monomer chosen from hydroxyalkyl methacrylates or acrylates (hydroxyalkyl, generally C 2 -C 8 ), advantageously hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxybutyl methacrylate (HBMA), hydroxyhexyl methacrylate (HHMA). As C1-C12 alkyl methacrylate (hydrophobic monomer), it is advantageously recommended to use methyl methacrylate (MMA), ethyl methacrylate (EMA), (n) -propyl methacrylate (PMA, n-PMA), (n) -butyl methacrylate (BMA, n-BMA), (n) -hexyl methacrylate (HMA, n-HMA), (n) -dodecyl methacrylate (DMA, n- DMA).
D'autres monomères hydrophiles (non acryliques) peuvent également intervenir pour élaborer des hydrogels convenant aux fins de l'invention. De façon nullement limitative, on peut citer la N-vinyl pyrrolidone et l'acrylamide. La réticulation est obtenue par l'intervention classique d'un réticulant lors de la mise en oeuvre de la réaction de copolymérisation. A titre de réticulants convenables, on peut citer, de façon nullement limitative, le diméthacrylate d'éthylène glycol, le diméthacrylate de dibutanediol et le diméthacrylate d'hexanediol. La réticulation est généralement menée en absence d'oxygène. Il est alors plus facile de la contrôler et l'on obtient ainsi des produits plus purs.Other hydrophilic (non-acrylic) monomers can also be used to prepare hydrogels suitable for the purposes of the invention. In no way limiting, mention may be made of N-vinyl pyrrolidone and acrylamide. Crosslinking is obtained by the conventional intervention of a crosslinking agent during the implementation of the copolymerization reaction. As suitable crosslinkers, there may be mentioned, in a nonlimiting manner, ethylene glycol dimethacrylate, dibutanediol dimethacrylate and hexanediol dimethacrylate. Crosslinking is generally carried out in the absence of oxygen. It is then easier to control it and we obtain purer products.
Les copolymères réticulés obtenus à partir de mélanges de monomères : methacrylate d'alkyle en C\ -Ci 2 / methacrylate d'hydroxyéthyle (HEMA) methacrylate d'alkyle en C1-C12 / methacrylate d'hydroxypropyle (HPMA) sont particulièrement préférés.Crosslinked copolymers obtained from mixtures of monomers: C 1 -C 2 alkyl methacrylate / hydroxyethyl methacrylate (HEMA) C 1 -C 12 alkyl methacrylate / hydroxypropyl methacrylate (HPMA) are particularly preferred.
Le monomère hydrophobe retenu peut consister en le methacrylate de méthyle (MMA) dont le polymère est à ce jour le seul matériau utilisé pour la fabrication de dispositifs de mise en tension de la capsule cristallinienne. De façon surprenante, selon l'invention, "ledit polymère a pu être modifié" pour gagner en hydrophilie - et être ainsi capable de se charger et de libérer progressivement dans l'oeil des principes actifs - sans perdre trop en propriétés mécaniques. L'homme du métier, à partir des précisions ci-dessus, est capable d'élaborer un hydrogel, dans lequel peut être taillé un dispositif de mise en tension de la capsule cristallinienne convenable. De façon classique, les hydrogels les moins hydrophiles libèrent, une fois chargés, leur charge en principe(s) actif(s) sur une plus longue période. Lesdits hydrogels les moins hydrophiles sont toutefois ceux que l'on ne peut guère charger en principe(s) actif(s). L'homme du métier saura adapter les caractéristiques de l'hydrogel à la nature du(des) principe(s) actif(s) intervenant(s) pour optimiser la libération de celui-ci(ceux-ci).The hydrophobic monomer retained may consist of methyl methacrylate (MMA), the polymer of which is to date the only material used for the manufacture of devices for tensioning the crystalline capsule. Surprisingly, according to the invention, "said polymer could have been modified" to gain hydrophilicity - and thus be able to charge and gradually release active ingredients in the eye - without losing too much in mechanical properties. A person skilled in the art, from the above details, is capable of developing a hydrogel, from which can be cut a device for tensioning the suitable crystalline capsule. Conventionally, the least hydrophilic hydrogels release, once charged, their charge in active principle (s) over a longer period. Said less hydrophilic hydrogels are, however, those which can hardly be charged in active principle (s). A person skilled in the art will know how to adapt the characteristics of the hydrogel to the nature of the active ingredient (s) involved in order to optimize the release thereof (these).
On note incidemment que pour renforcer les propriétés mécaniques d'un tel dispositif, rendu hydrophile, on peut jouer sur son épaisseur. Ainsi, l'épaisseur des dispositifs de l'invention peut-elle être supérieure à celle des dispositifs du même type de l'art antérieur. Ladite épaisseur reste bien évidemment compatible avec leur introduction dans le sac vidé. Il convient en fait d'une part de pouvoir implanter lesdits dispositifs et d'autre part que ceux-ci, une fois implantés, exercent sur les parois de la cavité cristallienne une force de tension suffisante ... mais non excessive.Incidentally, it is noted that in order to reinforce the mechanical properties of such a device, made hydrophilic, one can play on its thickness. Thus, the thickness of the devices of the invention can be greater than that of devices of the same type of the prior art. Said thickness obviously remains compatible with their introduction into the emptied bag. It is in fact advisable on the one hand to be able to implant said devices and on the other hand that these, once implanted, exert on the walls of the crystalline cavity a sufficient tension force ... but not excessive.
Les hydrogels dont la nature a été précisée ci-dessus conviennent pour représenter 100 % de la masse des dispositifs de l'invention. Ils conviennent évidemment pour ne représenter qu'une partie de ladite masse. Dans le cadre de la seconde variante des dispositifs de l'invention, on préconise de faire avantageusement intervenir à titre de matériau hydrophobe non biorésorbable du polyméthacrylate de méthyle (PMMA). Ledit matériau hydrophobe intervenant doit évidemment être compatible avec l'hydrogel intervenant (pouvoir se lier chimiquement avec ledit hydrogel).The hydrogels whose nature has been specified above are suitable for representing 100% of the mass of the devices of the invention. They are obviously suitable for representing only part of said mass. In the context of the second variant of the devices of the invention, it is recommended to use advantageously, as non-bioresorbable hydrophobic material, polymethyl methacrylate (PMMA). Said intervening hydrophobic material must obviously be compatible with the intervening hydrogel (being able to bond chemically with said hydrogel).
Le chargement en principe(s) actif(s) de l'hydrogel (des hydrogels) intervenant(s) dans la masse des dispositifs de l'invention ne soulève aucune difficulté particulière. Ceci est expliqué ci-après dans la présentation d'un procédé d'élaboration de dispositifs de l'invention chargés.The loading in principle (s) active (s) of the hydrogel (hydrogels) intervening (S) in the mass of the devices of the invention does not raise any particular difficulty. This is explained below in the presentation of a process for developing loaded devices of the invention.
Comme précisé ci-dessus, le(s) volume(s) d'hydrogel chargé(s), une fois le dispositif de l'invention mis en place dans la cavité cristallinienne, va(vont) libérer sa (leur) charge(s) de principe(s) actif(s) au travers de la(des) surface(s) d'échange qu'il(s) présente(nt) avec l'extérieur. Il peut être souhaitable d'intervenir pour modifier (ralentir) la cinétique de cet échange, de cette libération de(s) principe(s) actif(s) (libération qui, en tout état de cause, est appelée à se faire progressivement, par diffusion). A cette fin, on prévoit avantageusement l'intervention d'un revêtement de surface sur au moins une partie de ladite surface d'échange (surface d'échange totale, entre le(s) volume(s) d'hydrogel et l'extérieur, qui peut être la somme de plusieurs surfaces discontinues). Cette technique du revêtement de surface, pour optimiser une libération contrôlée progressive de principe actif est per se une technique connue. Dans le cadre de la présente invention, on a plus particulièrement développé deux voies pour générer un revêtement. Une première voie a consisté à absorber à la surface d'un dispositif de l'invention un mélange réactionnel d'acryliques, puis à faire polymériser ce mélange. Par interpénétration des réseaux de polymères, on crée ainsi en surface du(des) volume(s) d'hydrogel une membrane plus hydrophobe capable de ralentir la libération du(des) principe(s) actif(s). La deuxième voie a consisté à déposer à ladite surface d'un dispositif de l'invention un polymère ou un copolymere biorésorbable. De tels (co)polymères sont parfaitement connus de l'homme de métier. On préconise notamment à ce niveau l'intervention d'un (co)polymère type poly-α-hydroxyacide(s) et plus particulièrement celle d'un copolymere d'acides lactique et glycolique (par exemple 50/50). De tels poly-α-hydroxyacides sont notamment utilisés dans le domaine biomédical, pour, par exemple, la fabrication de plaques d'ostéosynthèse ou de fils de suture biorésorbables. Il est judicieux de choisir comme précurseur d'un tel revêtement biorésorbable des produits solubles dans des solvants, notamment organiques tels le tétrahydrofuranne et le dioxane, dans lesquels les principes actifs intervenants sont insolubles. Pour générer le revêtement souhaité, les dispositifs de l'invention, chargés en principe(s) actif(s) sont alors simplement immergés dans une solution de polymère relativement concentrée, puis retirés. Après évaporation du solvant, il reste une couche de polymère à la surface desdits dispositifs, notamment à la surface d'échange du(des) volume(s) d'hydrogel. Ainsi, quelle que soit leur variante de réalisation, les dispositifs de l'invention chargés peuvent comporter sur au moins une partie (généralement la totalité) de leur surface d'échange : volume(s) d'hydrogel(s) chargé(s) / extérieur, un revêtement de surface, destiné à ralentir la libération du(des) principe(s) actif(s) présent(s) dans le(les)dit(s) volume(s) d'hydrogel. On a par ailleurs remarqué qu'un tel revêtement intervient généralement aussi sur la régularité de ladite libération. Un tel revêtement consiste avantageusement en une couche ou membrane d'un polymère plus hydrophobe que l'hydrogel qu'il recouvre (voir la première voie présentée ci-dessus) ou en un polymère biorésorbable (voir la seconde voie présentée ci-dessus, préférée).As specified above, the volume (s) of hydrogel charged, once the device of the invention placed in the crystalline cavity, will (will) release its (their) charge (s) ) of active principle (s) through the exchange surface (s) that it (s) present (s) with the outside. It may be desirable to intervene to modify (slow down) the kinetics of this exchange, of this release of active principle (s) (release which, in any event, is called to take place gradually, by broadcast). To this end, provision is advantageously made for the intervention of a surface coating on at least part of said exchange surface (total exchange surface, between the volume (s) of hydrogel and the exterior. , which can be the sum of several discontinuous surfaces). This technique of surface coating, to optimize a gradual controlled release of active ingredient is per se a known technique. In the context of the present invention, two routes have more particularly been developed for generating a coating. A first route consisted in absorbing on the surface of a device of the invention a reaction mixture of acrylics, then in polymerizing this mixture. By interpenetration of the polymer networks, a more hydrophobic membrane capable of slowing the release of the active principle (s) is thus created on the surface of the volume (s) of hydrogel. The second route consisted in depositing on said surface of a device of the invention a bioresorbable polymer or copolymer. Such (co) polymers are perfectly known to those skilled in the art. It is particularly recommended at this level the intervention of a (co) polymer type poly-α-hydroxy acid (s) and more particularly that of a copolymer of lactic and glycolic acids (for example 50/50). Such poly-α-hydroxy acids are used in particular in the biomedical field, for, for example, the manufacture of osteosynthesis plates or bioresorbable sutures. It is judicious to choose as precursor of such a bioresorbable coating products soluble in solvents, in particular organic such as tetrahydrofuran and dioxane, in which the active active ingredients are insoluble. To generate the desired coating, the devices of the invention, loaded with active principle (s), are then simply immersed in a relatively concentrated polymer solution, then removed. After evaporation of the solvent, a layer of polymer remains on the surface of said devices, in particular on the exchange surface of the hydrogel volume (s). Thus, whatever their variant embodiment, the charged devices of the invention may comprise on at least part (generally all) of their exchange surface: volume (s) of hydrogel (s) charged (s) / exterior, a surface coating, intended to slow the release of the active ingredient (s) present in the said volume (s) of hydrogel. It has also been noted that such a coating generally also affects the regularity of said release. Such a coating advantageously consists of a layer or membrane of a more hydrophobic polymer than the hydrogel which it covers (see the first route presented above) or of a bioresorbable polymer (see the second route presented above, preferred ).
Les dispositifs de mise en tension de la capsule cristallinienne selon l'invention sont originaux en ce qu'un hydrogel non biorésorbable, susceptible d'être chargé en principe(s) actif(s), entre dans leur structure monobloc non biodégradable, voire constitue ladite structure. Ils ne présentent a priori guère d'originalité au niveau de leur géométrie. On rappelle toutefois ici qu'ils peuvent présenter une section supérieure à celle des dispositifs connus de l'art antérieur. Ils peuvent également ne pas présenter un profil uniforme sur toute leur longueur. Pour gagner en souplesse, ils peuvent présenter un profil affiné en au moins une zone. En tout état de cause, ils présentent des formes globales tout à fait similaires à celles desdits dispositifs connus et lesdites formes sont convenablement dimensionnées, par rapport aux dimensions de l'oeil de sorte que l'effet de mise en tension souhaité soit assuré. Ils peuvent notamment se présenter sous la forme d'anneaux ouverts, de section sensiblement circulaire ou polygonale à angles cassés; ils peuvent également se présenter sous la forme d'un morceau d'hélice (dont le pas est conséquent), dont la section peut également être sensiblement circulaire ou polygonale à angles cassés. Ils peuvent également avoir la forme d'une roue crantée, de section quelconque ...The devices for tensioning the lens capsule according to the invention are original in that a non-bioresorbable hydrogel capable of being charged with active principle (s) enters their non-biodegradable one-piece structure, or even constitutes said structure. A priori, they hardly present originality in terms of their geometry. However, it is recalled here that they may have a cross section greater than that of the devices known from the prior art. They may also not have a uniform profile over their entire length. To gain flexibility, they can present a refined profile in at least one zone. In any event, they have overall shapes quite similar to those of said known devices and said shapes are suitably sized, relative to the dimensions of the eye so that the desired tensioning effect is ensured. They can in particular be in the form of open rings, of substantially circular or polygonal section with broken angles; they can also be in the form of a piece of propeller (the pitch of which is substantial), the cross section of which can also be substantially circular or polygonal with broken angles. They can also have the shape of a toothed wheel, of any section ...
L'homme du métier aura compris, à la lecture de ce qui précède, que l'on dispose de deux principaux paramètres - le(s) matériau(x) intervenant(s) (nature, taux de réticulation ...) dans la structure du dispositif et la forme dudit dispositif - pour "régler" la tension que l'on souhaite voir exercer par ledit dispositif après son implantation.A person skilled in the art will have understood, on reading the above, that there are two main parameters - the material (s) involved (nature, crosslinking rate, etc.) in the structure of the device and the shape of said device - to "adjust" the tension that one wishes to see exerted by said device after implantation.
Selon un mode de réalisation de l'invention - mode de réalisation qui s'inscrit dans le cadre de la première variante, selon laquelle toute la masse du dispositif est en hydrogel - le dispositif de mise en tension de la capsule cristallinienne consiste en un anneau ouvert de section sensiblement circulaire ou polygonale à angles cassés, en hydrogel methacrylate d'hydroxyéthyle/méthacrylate de méthyle (HEMA/MMA) ou methacrylate d'hydroxypropyle/ methacrylate de méthyle (HPMA/MMA), chargé en au moins un principe actif et revêtu sur toute sa surface externe d'une couche biorésorbable d'un copolymere d'α-hydroxyacides.According to one embodiment of the invention - embodiment which is part of the first variant, according to which the entire mass of the device is in hydrogel - the device for tensioning the crystalline capsule consists of a ring open of substantially circular section or polygonal with broken angles, in hydroxyethyl methacrylate / methyl methacrylate (HEMA / MMA) or hydroxypropyl methacrylate / methyl methacrylate (HPMA / MMA), charged with at least one active principle and coated on its entire external surface d '' a bioresorbable layer of a copolymer of α-hydroxy acids.
Le dispositif de l'invention, quelle que soit sa variante de réalisation, est donc intéressant en ce qu'il est capable d'assurer efficacement la mise en tension de la capsule cristallinienne, pendant de nombreuses années (jusqu'à 20 ans et plus) tout en ayant, suite à son implantation, délivré progressivement dans ladite capsule au moins un principe actif. Ledit principe actif est introduit et libéré progressivement, de façon originale, via le(s) volume(s) d'hydrogel chargé(s) constituant toute ou partie de la masse dudit dispositif. Une telle libération progressive se substitue avantageusement à des injections répétées ...The device of the invention, whatever its variant of embodiment, is therefore advantageous in that it is capable of effectively ensuring the tensioning of the crystalline capsule, for many years (up to 20 years and more ) while having, following its implantation, progressively delivered into said capsule at least one active principle. Said active ingredient is introduced and gradually released, in an original manner, via the volume (s) of charged hydrogel (s) constituting all or part of the mass of said device. Such a gradual release advantageously replaces repeated injections ...
Au vu des complications biologiques associées à la chirurgie de la cataracte, rappelées ci-dessus, on préconise de faire intervenir les dispositifs de l'invention pour libérer progressivement au moins un antibiotique et/ou au moins un antimitotique et/ou au moins un inducteur de différentiation cellulaire terminale. Ainsi, l'hydrogel (les hydrogels) intervenant(s) à titre de constituant de sa masse referme(nt)-t-il(s) de façon séparée ou en combinaison, au moins un antibiotique et/ou moins un antimitotique et/ou au moins un inducteur de différentiation cellulaire.In view of the biological complications associated with cataract surgery, recalled above, it is recommended to use the devices of the invention to gradually release at least one antibiotic and / or at least one antimitotic and / or at least one inducer of terminal cell differentiation. Thus, does the hydrogel (hydrogels) acting as a constituent of its mass close (s) separately or in combination, at least one antibiotic and / or at least one antimitotic and / or at least one cell differentiation inducer.
Les dispositifs de l'invention, dont au moins un hydrogel susceptible d'être chargé constitue toute ou partie de la masse, peuvent évidemment renfermer ledit hydrogel chargé, dans un état plus ou moins hydraté, avant leur implantation. On préconise vivement d'implanter lesdits dispositifs chargés, à l'état sec. L'avantage d'implanter un tel dispositif sec est bien évidemment que la cinétique de libération du(des) principe(s) actif(s) est en outre limitée par la vitesse d'hydratation du matériau les renfermant.The devices of the invention, of which at least one hydrogel capable of being charged constitutes all or part of the mass, can obviously contain said charged hydrogel, in a more or less hydrated state, before their implantation. It is strongly recommended to install said loaded devices in the dry state. The advantage of installing such a dry device is obviously that the release kinetics of the active principle (s) is further limited by the rate of hydration of the material containing them.
On note incidemment ici que dans le cadre de la seconde variante de l'invention, selon laquelle une partie de la masse du dispositif n'est pas en hydrogel mais en un matériau hydrophobe, le passage du(des) volume(s) d'hydrogel, de l'état sec à l'état hydraté, ne génère guère de contraintes mécaniques dans la mesure où le(s)dit(s) volume(s) d'hydrogel n'est(ne sont) guère volumineux et présente(nt) toujours une surface d'échange avec l'extérieur. Un autre objet de la présente invention consiste en un procédé de préparation des dispositifs de l'invention, tels que décrits ci-dessus. Ledit procédé comprend :Incidentally, it is noted here that in the context of the second variant of the invention, according to which part of the mass of the device is not made of a hydrogel but of a hydrophobic material, the passage of the volume (s) of hydrogel, from the dry state to the hydrated state, hardly generates mechanical stresses insofar as the said volume (s) of hydrogel is (are) hardly bulky and present ( nt) always an exchange surface with the outside. Another object of the present invention consists in a process for preparing the devices of the invention, as described above. Said method comprises:
- la taille d'une forme appropriée dans une masse d'hydrogel non biorésorbable ou dans un matériau composite non biorésorbable adéquat comportant au moins un volume d'hydrogel non biorésorbable (matériau composite : hydrogel / matériau hydrophobe),the size of an appropriate shape in a non-bioresorbable hydrogel mass or in a suitable non-bioresorbable composite material comprising at least one volume of non-bioresorbable hydrogel (composite material: hydrogel / hydrophobic material),
- le nettoyage et éventuellement le séchage de ladite forme, pour l'obtention d'un dispositif non chargé; - l'immersion dans une solution chargée en principe(s) actif(s) pendant une durée suffisante dudit dispositif non chargé sec,- cleaning and possibly drying of said form, to obtain an unloaded device; - immersion in a solution loaded with active principle (s) for a sufficient duration of said dry uncharged device,
- son extraction de ladite solution et avantageusement son séchage,- its extraction from said solution and advantageously its drying,
- éventuellement, le dépôt d'un revêtement, destiné à ralentir la libération du(des)dit(s) principe(s) actif(s) chargé(s), à sa surface, pour l'obtention d'un dispositif chargé.- Optionally, the deposition of a coating, intended to slow the release of the said active principle (s) charged (s), on its surface, to obtain a charged device.
En amont dudit procédé, il convient bien évidemment de préparer le bloc de matériau adéquat : bloc d'hydrogel(s) ou bloc composite hydrogel(s)/ matériau(x) hydrophobe(s), au sein duquel les matériaux différents sont liés chimiquement et disposés de sorte à générer, à l'issue de la taille, une forme appropriée (dont le(s) volume(s) d'hydrogel présente(nt) au moins une surface d'échange avec l'extérieur).Upstream of said process, it is obviously necessary to prepare the block of suitable material: hydrogel block (s) or hydrogel composite block (s) / hydrophobic material (s), within which the different materials are chemically linked. and arranged so as to generate, at the end of the pruning, an appropriate shape (in which the volume (s) of hydrogel has (s) at least one surface for exchange with the outside).
La taille du dispositif de l'invention dans un tel bloc ne soulève aucune difficulté particulière. Ladite taille est généralement suivie d'un polissage, destiné à éliminer toute rugosité, tout angle vif de la forme taillée. Ladite forme taillée et généralement polie est alors nettoyée. Par le biais d'un tel nettoyage, on vise à la purifier, à en extraire tout résidu de polymérisation, dont la libération dans l'oeil (notamment iors de l'hydratation de l'hydrogel, qui est avantageusement introduit sec) serait dommageable. A l'issue d'un tel nettoyage, on obtient une forme qu'il est possible d'implanter, avantageusement hydratée, non chargée, pour la mise en tension de la capsule cristallinienne. Si l'on souhaite charger ladite forme, il est avantageux de la sécher préalablement, généralement par chauffage sous vide. A l'issue d'un tel séchage, on obtient le dispositif de l'invention non chargé qui peut être conservé en l'état pour une implantation ultérieure après chargement ou qu'il est possible de charger immédiatement. Pour un tel chargement en principe(s) actif(s), ladite forme sèche est immergée dans une solution renfermant le(s)dit(s) principe(s) actif(s). L'homme du métier maîtrise parfaitement une telle étape de chargement d'un hydrogel.The size of the device of the invention in such a block does not raise any particular difficulty. Said size is generally followed by a polishing, intended to eliminate any roughness, any sharp angle of the cut shape. Said cut and generally polished shape is then cleaned. By means of such cleaning, the aim is to purify it, to extract from it any polymerization residue, the release of which into the eye (in particular during hydration of the hydrogel, which is advantageously introduced dry) would be harmful. . After such cleaning, a form is obtained which it is possible to implant, advantageously hydrated, uncharged, for the tensioning of the lens capsule. If it is desired to load said form, it is advantageous to dry it beforehand, generally by heating under vacuum. At the end of such drying, the device of the invention which is not loaded is obtained which can be kept in the state for subsequent implantation after loading or which can be loaded immediately. For such a loading in active principle (s), said dry form is immersed in a solution containing the said active principle (s). A person skilled in the art perfectly masters such a step of loading a hydrogel.
Le dispositif chargé est extrait de la solution de chargement et peut être utilisé, implanté, tel quel.The charged device is extracted from the charging solution and can be used, implanted, as is.
On a vu qu'il est avantageusement implanté, à l'état sec et le procédé de l'invention comporte donc à ce niveau, avantageusement une étape de séchage du dispositif chargé.We have seen that it is advantageously implanted, in the dry state and the method of the invention therefore comprises, at this level, advantageously a step of drying the loaded device.
Eventuellement, ledit procédé de l'invention comporte une étape supplémentaire destinée à générer un revêtement à la surface du dispositif chargé obtenu. Des techniques de dépôt d'un tel revêtement ont été discutées en amont dans le présent texte. Elles sont en elles-mêmes parfaitement connues de l'homme du métier.Optionally, said method of the invention comprises an additional step intended to generate a coating on the surface of the charged device obtained. Techniques for depositing such a coating have been discussed upstream in the present text. They are in themselves perfectly known to those skilled in the art.
L'invention est illustrée, schématiquement, sur les figures annexées. La figure 1 est une vue en plan d'un dispositif de mise en tension de la capsule cristallinienne, selon l'invention.The invention is illustrated, schematically, in the appended figures. Figure 1 is a plan view of a device for tensioning the lens capsule, according to the invention.
La figure 2 est une section, prise suivant V -V de ladite figure 1. Les figures 3 à 6 sont des sections, prises suivant V - V de vues en plan, analogues à la figure 1, d'autres dispositifs de mise en tension de la capsule cristallinienne selon l'invention.Figure 2 is a section, taken along V-V of said figure 1. Figures 3 to 6 are sections, taken along V - V of plan views, similar to Figure 1, of other tensioning devices of the lens capsule according to the invention.
Les dispositifs représentés sur lesdites figures 1 à 6, et notamment le dispositif (1) des figures 1 et 2, sont des anneaux ouverts de section polygonale à angles cassés.The devices shown in said Figures 1 to 6, and in particular the device (1) of Figures 1 and 2, are open rings of polygonal section with broken angles.
Le dispositif (1) selon les figures 1 et 2 présente une structure monobloc en un hydrogel H, non biorésorbable, chargé en un principe actif (2). On a représenté schématiquement ledit principe actif (2) qui, en fait, est dispersé dans ledit hydrogel H.The device (1) according to Figures 1 and 2 has a one-piece structure in a hydrogel H, not bioresorbable, charged with an active principle (2). The active ingredient (2) is shown diagrammatically, which in fact is dispersed in the said hydrogel H.
Toute la surface externe dudit dispositif (1) constitue la surface d'échange par laquelle le principe actif (2) est susceptible d'être libéré. Les dispositifs de l'invention selon les figures 3 à 6 ont, de façon caractéristique, une partie de leur masse, présentant au moins une surface d'échange avec l'extérieur, en un hydrogel H, non biorésorbable, chargé en principe actif (2) et la partie complémentaire en un matériau hydrophobe non biorésorbable : M. Lesdits hydrogels H et matériaux hydrophobes M non biorésorbables des différents dispositifs représentés peuvent être identiques ou différents. Au sein d'un même dispositif, par exemple ceux selon les figures 4 à 6, on peut notamment faire intervenir deux matériaux hydrophobes non biorésorbables M différents.The entire external surface of said device (1) constitutes the exchange surface by which the active principle (2) is capable of being released. The devices of the invention according to FIGS. 3 to 6 typically have a part of their mass, having at least one surface for exchange with the outside, in a hydrogel H, not bioresorbable, charged with active principle ( 2) and the complementary part made of a non-bioresorbable hydrophobic material: M. Said hydrogels H and non-bioresorbable hydrophobic materials M of the different devices shown can be identical or different. Within of the same device, for example those according to FIGS. 4 to 6, it is in particular possible to involve two hydrophobic non-bioresorbable materials M.
Sur la figure 5, on a représenté en (3) un revêtement de surface , couvrant la surface d'échange entre l'hydrogel H chargé et l'extérieur. II est clair que les variantes de réalisation de l'invention montrées sur les figures annexées, ne sont nullement exhaustives.In Figure 5, there is shown in (3) a surface coating, covering the exchange surface between the charged hydrogel H and the outside. It is clear that the alternative embodiments of the invention shown in the appended figures are by no means exhaustive.
On illustre enfin l'invention présentement revendiquée par l'exemple ci- après.Finally, the invention currently illustrated is illustrated by the example below.
On a élaboré et testé un dispositif de l'invention comme précisé ci-après.A device of the invention has been developed and tested as specified below.
a) Synthèse de l'hydrogela) Synthesis of the hydrogel
30 g de methacrylate d'hydroxypropyle (HPMA : monomère hydrophile), 10 g de methacrylate de méthyle (MMA : monomère hydrophobe), 0,32 g de diméthacrylate d'éthylène glycol (agent de réticulation) et 0,08 g de peroxyde de benzoyle (initiateur de la réaction de copolymérisation) sont ajoutés dans un bêcher. Après homogénéisation, la solution est désoxygénée par bullage d'argon. Elle est ensuite versée dans une cavité, délimitée principalement par deux plaques de polypropylène espacées d'environ 4 mm. L'ensemble est mis au bain-marie 48 heures à 40°C. A l'issue de ces 48 heures, on élève la température du bain à 60°C et on maintient à nouveau pendant 48 heures, l'ensemble dans ledit bain à 60°C. A l'issue de ces nouvelles 48 heures, l'ensemble est retiré du bain-marie et placé dans une étuve à 100°C pour 24 heures. On maîtrise ainsi parfaitement la réaction de copolymérisation.30 g of hydroxypropyl methacrylate (HPMA: hydrophilic monomer), 10 g of methyl methacrylate (MMA: hydrophobic monomer), 0.32 g of ethylene glycol dimethacrylate (crosslinking agent) and 0.08 g of peroxide benzoyl (initiator of the copolymerization reaction) are added to a beaker. After homogenization, the solution is deoxygenated by bubbling argon. It is then poured into a cavity, mainly delimited by two polypropylene plates spaced about 4 mm apart. The whole is put in a water bath for 48 hours at 40 ° C. At the end of these 48 hours, the temperature of the bath is raised to 60 ° C. and the whole is maintained again for 48 hours in said bath at 60 ° C. At the end of these new 48 hours, the assembly is removed from the water bath and placed in an oven at 100 ° C. for 24 hours. This perfectly controls the copolymerization reaction.
Le matériau obtenu est extrait dans un mélange méthanol/eau : 50/50 en volume. On élimine ainsi les résidus de la polymérisation. La masse d'extractibles s'est révélée être de 3,7 %. La teneur en eau de l'hydrogel hydraté préparé est de 15,5 % en masse.The material obtained is extracted in a methanol / water mixture: 50/50 by volume. This removes the residue from the polymerization. The mass of extractables was found to be 3.7%. The water content of the hydrated hydrogel prepared is 15.5% by mass.
b) Taille du dispositif de l'invention. Son chargement en principe actif. Un anneau de 12 mm de diamètre externe et de 0,7 x 0,7 mm de section est taillé dans le matériau obtenu à l'issue de la synthèse décrite ci-dessus. Ledit anneau de section constante est éventuellement repris, pour être aminci en certains endroits; ceci dans le but d'ajuster ses propriétés mécaniques. La masse de l'implant intraoculaire (déshydraté) ainsi obtenu est de 16,5 mg. Ledit implant déshydraté est placé dans une solution aqueuse renfermantb) Size of the device of the invention. Its active principle loading. A ring with an external diameter of 12 mm and a section of 0.7 x 0.7 mm is cut from the material obtained at the end of the synthesis described above. Said ring of constant section may be taken up again, to be thinned in certain places; this in order to adjust its mechanical properties. The mass of the intraocular implant (dehydrated) thus obtained is 16.5 mg. Said dehydrated implant is placed in an aqueous solution containing
40 mg/ml de 5-fluorouracil (5-FU). Lorsque l'hydratation est achevée, l'implant est retiré de ladite solution et mis dans une étuve, sous vide, pour son séchage. La quantité de 5-FU retenue dans l'implant (chargé) est de 250 μg.40 mg / ml 5-fluorouracil (5-FU). When hydration is complete, the implant is removed from said solution and placed in an oven, under vacuum, for drying. The quantity of 5-FU retained in the implant (loaded) is 250 μg.
c) Revêtement L'implant chargé sec est plongé dans du tétrahydrofuranne contenantc) Coating The dry loaded implant is immersed in tetrahydrofuran containing
10 % en masse d'un copolymere d'acides lactique et glycolique (50/50). L'implant est ensuite retiré de ladite solution puis séché. Le solvant évaporé laisse un dépôt de copolymere à la surface dudit implant.10% by mass of a copolymer of lactic and glycolic acids (50/50). The implant is then removed from said solution and dried. The evaporated solvent leaves a copolymer deposit on the surface of said implant.
d) Libération du principe actifd) Release of the active ingredient
L'implant sec est placé dans un flacon contenant 5 ml de sérum physiologique, ce volume correspondant au volume moyen d'un oeil. La solution est régulièrement remplacée et le 5-FU est dosée dans la solution ainsi récupérée. La durée nécessaire à la libération totale du 5-FU chargé est de 9 jours. SeulementThe dry implant is placed in a bottle containing 5 ml of physiological saline, this volume corresponding to the average volume of one eye. The solution is regularly replaced and the 5-FU is dosed in the solution thus recovered. The time required for full release of the loaded 5-FU is 9 days. Only
20 % dudit 5-FU chargé est libéré dans les deux premières heures.20% of said charged 5-FU is released within the first two hours.
Avec un anneau tout à fait similaire, taillé dans le même matériau, chargé dans des conditions identiques mais non plongé dans la solution de copolymere acide lactique/acide glycolique - non revêtu - la durée nécessaire à la libération totale du 5-FU est de 7 jours, avec 70 % dudit 5-FU libéré dans les deux premières heures. With a completely similar ring, cut from the same material, loaded under identical conditions but not immersed in the solution of lactic acid / glycolic acid copolymer - uncoated - the time required for the total release of the 5-FU is 7 days, with 70% of said 5-FU released within the first two hours.

Claims

- Revendications - - Claims -
1. Dispositif de mise en tension de la capsule cristallinienne, susceptible d'être chargé en au moins un principe actif et de libérer progressivement ledit principe actif, caractérisé en ce qu'au moins un volume d'hydrogel non biorésorbable, susceptible d'être chargé en principe(s) actif(s), constitue toute ou partie de la masse monobloc non biorésorbable dudit dispositif, en présentant au moins une surface d'échange avec l'extérieur.1. Device for tensioning the crystalline capsule, capable of being loaded with at least one active principle and of progressively releasing said active principle, characterized in that at least one volume of non-bioresorbable hydrogel capable of being charged in principle (s) active (s), constitutes all or part of the non-bioabsorbable one-piece mass of said device, having at least one surface for exchange with the outside.
2. Dispositif de mise en tension de la capsule cristallinienne selon la revendication 1, caractérisé en ce que toute la masse dudit dispositif est en hydrogel non biorésorbable, avantageusement en ce qu'un unique hydrogel non biorésorbable susceptible d'être chargé en principe(s) actif(s) constitue toute ladite masse.2. A device for tensioning the crystalline capsule according to claim 1, characterized in that the entire mass of said device is made of a non-bioresorbable hydrogel, advantageously in that a single non-bioresorbable hydrogel capable of being charged in principle (s ) active (s) constitutes all of said mass.
3. Dispositif de mise en tension de la capsule cristallinienne selon la revendication 1, caractérisé en ce qu'une partie de la masse dudit dispositif est en un matériau hydrophobe non biorésorbable.3. Device for tensioning the crystalline capsule according to claim 1, characterized in that part of the mass of said device is made of a non-bioresorbable hydrophobic material.
4. Dispositif de mise en tension de la capsule cristallinienne selon l'une quelconque des revendications 1 à 3, caractérisé en ce que ledit hydrogel est un copolymere acrylique hydrophile réticulé. 4. Device for tensioning the crystalline capsule according to any one of claims 1 to 3, characterized in that said hydrogel is a crosslinked hydrophilic acrylic copolymer.
5. Dispositif de mise en tension de la capsule cristallinienne selon l'une quelconque des revendications 1 à 4, caractérisé en ce que ledit hydrogel est un copolymere réticulé obtenu à partir d'un mélange d'au moins un monomère hydrophobe choisi parmi les méthacrylates ou acrylates d'alkyle, avantageusement les méthacrylates d'alkyle en C^-C^ et d'au moins un monomère hydrophile choisi parmi les méthacrylates ou acrylates d'hydroxyalkyle, avantageusement le methacrylate d'hydroxyéthyle (HEMA), le methacrylate d'hydroxypropyle (HPMA), le methacrylate d'hydroxybutyle (HBMA), le methacrylate d'hydroxyhexyle (HHMA).5. Device for tensioning the crystalline capsule according to any one of claims 1 to 4, characterized in that said hydrogel is a crosslinked copolymer obtained from a mixture of at least one hydrophobic monomer chosen from methacrylates or alkyl acrylates, advantageously C 1 -C 4 alkyl methacrylates and of at least one hydrophilic monomer chosen from hydroxyalkyl methacrylates or acrylates, advantageously hydroxyethyl methacrylate (HEMA), methacrylate hydroxypropyl (HPMA), hydroxybutyl methacrylate (HBMA), hydroxyhexyl methacrylate (HHMA).
6. Dispositif de mise en tension de la capsule cristallinienne selon l'une quelconque des revendications 1 à 5, caractérisé en ce que ledit hydrogel est un copolymere réticulé obtenu à partir d'un mélange d'un methacrylate d'alkyle en l -Ci 2 et de methacrylate d'hydroxyéthyle (HEMA) ou d'hydroxypropyle (HPMA).6. Device for tensioning the crystalline capsule according to any one of claims 1 to 5, characterized in that said hydrogel is a crosslinked copolymer obtained from a mixture of an alkyl methacrylate in 1 -C 1 2 and hydroxyethyl methacrylate (HEMA) or hydroxypropyl (HPMA).
7. Dispositif de mise en tension de la capsule cristallinienne selon l'une quelconque des revendications 1 à 6, caractérisé en ce que la surface d'échange, entre le(s) volume(s) d'hydrogel chargé(s) en principe(s) actif(s) et l'extérieur est au moins en partie recouverte d'un revêtement de surface, destiné à ralentir la libération du(des)dit(s) principe(s) actif(s).7. Device for tensioning the crystalline capsule according to any one of claims 1 to 6, characterized in that the exchange surface, between the volume (s) of hydrogel charged (s) in principle (s) active and the exterior is at least partially covered with a surface coating, intended to slow the release of the said active ingredient (s).
8. Dispositif de mise en tension de la capsule cristallinienne selon la revendication 7, caractérisé en ce que ledit revêtement de surface consiste en une couche ou membrane d'un polymère plus hydrophobe que ledit hydrogel ou d'un (co)polymère biorésorbable.8. Device for tensioning the crystalline capsule according to claim 7, characterized in that said surface coating consists of a layer or membrane of a more hydrophobic polymer than said hydrogel or of a bioresorbable (co) polymer.
9. Dispositif de mise en tension de la capsule cristallinienne selon l'une des revendications 7 ou 8, caractérisé en ce que ledit revêtement de surface consiste en une couche ou membrane d'un (co)polymère d'α-hydroxyacide(s). 9. Device for tensioning the crystalline capsule according to one of claims 7 or 8, characterized in that said surface coating consists of a layer or membrane of a (co) polymer of α-hydroxy acid (s) .
10. Dispositif de mise en tension de la capsule cristallinienne selon l'une quelconque des revendications 1 à 9, caractérisé en ce que ledit hydrogel est chargé en au moins un antibiotique et/ou un antimitotique et/ou un inducteur de différentiation cellulaire terminale.10. Device for tensioning the crystalline capsule according to any one of claims 1 to 9, characterized in that said hydrogel is loaded with at least one antibiotic and / or an antimitotic and / or an inducer of terminal cell differentiation.
11. Dispositif de mise en tension de la capsule cristallinienne selon l'une quelconque des revendications 1 à 10, à l'état sec.11. Device for tensioning the crystalline capsule according to any one of claims 1 to 10, in the dry state.
12. Procédé pour la préparation d'un dispositif de mise en tension de la capsule cristallinienne selon l'une quelconque des revendications 1 à 11, caractérisé en ce qu'il comprend :12. Process for the preparation of a device for tensioning the crystalline capsule according to any one of claims 1 to 11, characterized in that it comprises:
- la taille d'une forme appropriée dans une masse d'hydrogel non biorésorbable ou dans un matériau composite non biorésorbable adéquat comportant au moins un volume d'hydrogel non biorésorbable,the size of an appropriate shape in a mass of non-bioresorbable hydrogel or in a suitable non-bioresorbable composite material comprising at least one volume of non-bioresorbable hydrogel,
- le nettoyage et éventuellement le séchage de ladite forme, pour l'obtention dudit dispositif non chargé;- cleaning and possibly drying of said form, to obtain said unloaded device;
- l'immersion dans une solution chargée en principe(s) actif(s) pendant une durée suffisante de ladite forme séchée,- immersion in a solution loaded with active principle (s) for a sufficient duration of said dried form,
- son extraction de ladite solution et avantageusement son séchage,- its extraction from said solution and advantageously its drying,
- éventuellement, le dépôt d'un revêtement, destiné à ralentir la libération du(des)dit(s) principe(s) actif(s) chargé(s), à sa surface, pour l'obtention dudit dispositif chargé. - Optionally, the deposition of a coating, intended to slow the release of said active principle (s) charged, on its surface, to obtain said charged device.
PCT/FR1997/001785 1996-10-07 1997-10-07 Device for stretching the crystalline capsule, capable of being charged with at least one active principle and for releasing said active principle, and its preparation WO1998015238A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP97944934A EP0946125A1 (en) 1996-10-07 1997-10-07 Device for stretching the crystalline capsule, capable of being charged with at least one active principle and for releasing said active principle, and its preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR96/12174 1996-10-07
FR9612174A FR2754173B1 (en) 1996-10-07 1996-10-07 DEVICE FOR TENSIONING THE CRYSTALLINE CAPSULE, LIKELY TO BE CHARGED WITH AT LEAST ONE ACTIVE PRINCIPLE AND TO RELEASE THE ACTIVE PRINCIPLE, AND ITS PREPARATION

Publications (1)

Publication Number Publication Date
WO1998015238A1 true WO1998015238A1 (en) 1998-04-16

Family

ID=9496403

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR1997/001785 WO1998015238A1 (en) 1996-10-07 1997-10-07 Device for stretching the crystalline capsule, capable of being charged with at least one active principle and for releasing said active principle, and its preparation

Country Status (3)

Country Link
EP (1) EP0946125A1 (en)
FR (1) FR2754173B1 (en)
WO (1) WO1998015238A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6187042B1 (en) 1998-04-15 2001-02-13 Alcon Laboratories, Inc. Intraocular lens coating compositions
US6210438B1 (en) * 1998-04-15 2001-04-03 Alcon Laboratories, Inc. Bicomposite intraocular lens and method for its preparation
US6416550B2 (en) 1998-04-15 2002-07-09 Alcon Manufacturing, Ltd. Method of selecting an intraocular lens material
WO2002064071A1 (en) * 2001-02-13 2002-08-22 The Lions Eye Institute Of Western Australia Device and method for anterior segment drug delivery
US6455318B1 (en) 1998-04-15 2002-09-24 Alcon Manufacturing, Ltd. Collagen IV adhesion assay for intraocular lens materials
US6482230B1 (en) 1998-04-15 2002-11-19 Alcon Manufacturing, Ltd. Lens epithelial cell growth assay for intraocular lens materials
US6491721B2 (en) 1998-04-15 2002-12-10 Alcon Manufacturing, Ltd. Toric intraocular lens material
WO2016079204A1 (en) 2014-11-18 2016-05-26 Pierre Coulon Multifunctional capsular implant

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19724108C1 (en) 1997-06-09 1998-11-19 Morcher Gmbh Capsule equatorial ring
US5843184A (en) * 1998-01-26 1998-12-01 Cionni; Robert J. Endocapsular tension ring and method of implanting same
FR2784287B1 (en) * 1998-10-13 2000-12-08 Georges Baikoff SCLERAL EXPANSION SEGMENT
FR2801192B1 (en) * 1999-11-19 2002-08-09 Corneal Ind RING FOR CAPSULAR BAG AND ASSEMBLY CONSISTING OF SUCH A RING AND ITS INJECTOR
DE102004027236B4 (en) * 2004-06-03 2006-04-13 Morcher Gmbh Capsular equatorial ring

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4731080A (en) * 1985-01-18 1988-03-15 Galin Miles A Coated intraocular lens
EP0443809A2 (en) * 1990-02-20 1991-08-28 Ioptex Research Inc. Coated intraocular lens and coatings therefor
EP0478929A1 (en) * 1990-09-29 1992-04-08 Ipp Intellectual Property Protection Ag Device for positioning an intraocular lens
EP0507292A1 (en) * 1991-04-04 1992-10-07 Menicon Co., Ltd. Device for inhibiting aftercataract
WO1995003755A1 (en) * 1993-08-02 1995-02-09 Keravision, Inc. Segmented preformed intrastromal corneal insert
EP0732090A1 (en) * 1995-03-15 1996-09-18 LANGERMAN, David W. Spare parts for use in ophthalmic surgical procedures

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4731080A (en) * 1985-01-18 1988-03-15 Galin Miles A Coated intraocular lens
EP0443809A2 (en) * 1990-02-20 1991-08-28 Ioptex Research Inc. Coated intraocular lens and coatings therefor
EP0478929A1 (en) * 1990-09-29 1992-04-08 Ipp Intellectual Property Protection Ag Device for positioning an intraocular lens
EP0507292A1 (en) * 1991-04-04 1992-10-07 Menicon Co., Ltd. Device for inhibiting aftercataract
WO1995003755A1 (en) * 1993-08-02 1995-02-09 Keravision, Inc. Segmented preformed intrastromal corneal insert
EP0732090A1 (en) * 1995-03-15 1996-09-18 LANGERMAN, David W. Spare parts for use in ophthalmic surgical procedures

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6187042B1 (en) 1998-04-15 2001-02-13 Alcon Laboratories, Inc. Intraocular lens coating compositions
US6210438B1 (en) * 1998-04-15 2001-04-03 Alcon Laboratories, Inc. Bicomposite intraocular lens and method for its preparation
US6416550B2 (en) 1998-04-15 2002-07-09 Alcon Manufacturing, Ltd. Method of selecting an intraocular lens material
US6455318B1 (en) 1998-04-15 2002-09-24 Alcon Manufacturing, Ltd. Collagen IV adhesion assay for intraocular lens materials
US6482230B1 (en) 1998-04-15 2002-11-19 Alcon Manufacturing, Ltd. Lens epithelial cell growth assay for intraocular lens materials
US6491721B2 (en) 1998-04-15 2002-12-10 Alcon Manufacturing, Ltd. Toric intraocular lens material
WO2002064071A1 (en) * 2001-02-13 2002-08-22 The Lions Eye Institute Of Western Australia Device and method for anterior segment drug delivery
WO2016079204A1 (en) 2014-11-18 2016-05-26 Pierre Coulon Multifunctional capsular implant

Also Published As

Publication number Publication date
FR2754173B1 (en) 1998-12-24
FR2754173A1 (en) 1998-04-10
EP0946125A1 (en) 1999-10-06

Similar Documents

Publication Publication Date Title
WO1998015238A1 (en) Device for stretching the crystalline capsule, capable of being charged with at least one active principle and for releasing said active principle, and its preparation
US6976997B2 (en) Artificial cornea
CA2770356C (en) Intraocular lenses with interlenticular opacification resistance
WO1998013050A1 (en) Surface modified surgical instruments, medical devices, implants, contact lenses and the like
CA3002914C (en) Acrylic copolymer, which is hydrophobic, cross-linked and based on cinnamic alcohol, for intraocular lenses
FR2930731A1 (en) ACRYLIC POLYMERIC MATERIAL, HYDROPHOBIC FOR INTRAOCULAR LENS
EP3110464B1 (en) Crosslinked, hydrophobic acrylic copolymer made of 2-phenoxy-tetraethylene-glycol acrylate and intended for intraocular lenses
FR2897775A1 (en) Gel composition for manufacturing medical device used in persons suffering from stress urinary incontinence, contains bioresorbable polysaccharide, and resorbable particles comprising chitin and/or chitosan
EP1001743A1 (en) Implants for controlled release of pharmaceutically active principles and method for making same
CA2274942C (en) Intraocular lens containing releasable medication
FR2608041A1 (en) KERATO-PROSTHESIS INTENDED TO BE IMPLANTED IN THE CORNEA AND METHOD FOR MANUFACTURING THE SAME
WO2016079204A1 (en) Multifunctional capsular implant
EP1003446B1 (en) Implant forming bi-material single-piece intraocular lens
WO2017103241A1 (en) Hyaluronic acid composition for penile injections
EP1567205B1 (en) Composite prosthesis
WO1998013051A1 (en) Ocular implants and methods for their manufacture
WO2000029042A1 (en) Injection implant comprising porous microparticles
FR2836921A1 (en) A method of preparing an injectable foam for use in creating implants, especially for the prevention of incontinence by mixing a polymer and swelling agent, heating, grinding and mixing with a support
Laugier et al. Biliary and pancreatic stents: indications, results and techniques
Bouétel et al. Complémentarité des techniques implantaires et piézographiques en prothèse amovible complète

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1997944934

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1997944934

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: CA

WWR Wipo information: refused in national office

Ref document number: 1997944934

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1997944934

Country of ref document: EP