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WO2013038119A2 - Device for storing and dispensing liquid - Google Patents

Device for storing and dispensing liquid Download PDF

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Publication number
WO2013038119A2
WO2013038119A2 PCT/FR2012/052079 FR2012052079W WO2013038119A2 WO 2013038119 A2 WO2013038119 A2 WO 2013038119A2 FR 2012052079 W FR2012052079 W FR 2012052079W WO 2013038119 A2 WO2013038119 A2 WO 2013038119A2
Authority
WO
WIPO (PCT)
Prior art keywords
coating
poly
molecules
prostaglandin
liquid
Prior art date
Application number
PCT/FR2012/052079
Other languages
French (fr)
Other versions
WO2013038119A3 (en
Inventor
Thierry Rimlinger
Pascal Dugand
Nolwenn Stephan
Original Assignee
Rexam Healthcare La Verpilliere
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 Rexam Healthcare La Verpilliere filed Critical Rexam Healthcare La Verpilliere
Publication of WO2013038119A2 publication Critical patent/WO2013038119A2/en
Publication of WO2013038119A3 publication Critical patent/WO2013038119A3/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D183/00—Coating compositions based on macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon, with or without sulfur, nitrogen, oxygen, or carbon only; Coating compositions based on derivatives of such polymers
    • C09D183/04—Polysiloxanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D171/00—Coating compositions based on polyethers obtained by reactions forming an ether link in the main chain; Coating compositions based on derivatives of such polymers
    • C09D171/02—Polyalkylene oxides
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D183/00—Coating compositions based on macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon, with or without sulfur, nitrogen, oxygen, or carbon only; Coating compositions based on derivatives of such polymers
    • C09D183/04—Polysiloxanes
    • C09D183/08—Polysiloxanes containing silicon bound to organic groups containing atoms other than carbon, hydrogen, and oxygen
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
    • C09D5/14—Paints containing biocides, e.g. fungicides, insecticides or pesticides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/1468—Containers characterised by specific material properties
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
    • C08G77/04—Polysiloxanes
    • C08G77/22—Polysiloxanes containing silicon bound to organic groups containing atoms other than carbon, hydrogen and oxygen
    • C08G77/24—Polysiloxanes containing silicon bound to organic groups containing atoms other than carbon, hydrogen and oxygen halogen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
    • C08G77/80—Siloxanes having aromatic substituents, e.g. phenyl side groups
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D101/00—Coating compositions based on cellulose, modified cellulose, or cellulose derivatives
    • C09D101/08—Cellulose derivatives
    • C09D101/26—Cellulose ethers
    • C09D101/28—Alkyl ethers
    • C09D101/284—Alkyl ethers with hydroxylated hydrocarbon radicals

Definitions

  • the present invention relates to a device for storing and dispensing pharmaceutical liquid such as ophthalmic liquid.
  • the ophthalmic liquid comprises, as active principle, at least one prostaglandin or a prostaglandin analogue, especially for the treatment of glaucoma.
  • Prostaglandins or prostaglandin analogues are well known active ingredients, generally administered to humans or animals topically in the form of eye drops for the treatment of glaucoma. These active ingredients can also be used in combination with a second anti-glaucoma agent such as, for example, a beta-blocker, a carbonic anhydrase inhibitor or an alpha-adrenergic agonist.
  • a second anti-glaucoma agent such as, for example, a beta-blocker, a carbonic anhydrase inhibitor or an alpha-adrenergic agonist.
  • prostaglandins or prostaglandin analogues are not soluble in water, their dissolution in the preparation of eye drops presents some difficulties. Indeed, it is necessary to go through a preliminary step of solubilization of the active ingredient to obtain an aqueous solution ready to be distributed.
  • an anti-microbial preservative was often added.
  • these preservatives which could contribute to the solubilization of the active ingredient and its stabilization within the solution, are now deprecated because they can be toxic and pose problems of tolerance, especially in the context of a treatment of long-term such as the treatment of glaucoma. The solubilization of the active ingredient and its stability in the device is therefore likely to be affected.
  • the solution comprising the active ingredient must also be stable over time. Indeed, the liquid can be stored for up to thirty-six months in the device before its first opening, then about 1 month after its first opening, for example for administration at the rate of one drop in each eye per day.
  • a reduction in the concentration of active ingredient in the drops delivered is observed. This reduction in concentration may be due to absorption phenomena of the active ingredient in the parts of the device in contact with the solution and / or adsorption phenomena on these same parts. It may also be due to the absorption or adsorption of any other species present in the solution which could, by modifying the equilibrium of the solution, promote the adsorption or absorption of the active ingredient by parts of the solution. device in contact with the solution.
  • prostaglandins or prostaglandin analogues are generally introduced into the solution at low concentrations, such as a concentration of less than 1% by weight, or even less than 0.01% by weight.
  • One solution to this problem is to modify the formulation of the solution in order to make the solution stable and inert with respect to the material of the storage and dispensing device, even at low concentrations.
  • a device for dispensing product with or without a preservative for example, to comprise different polymer materials for the reservoir and for the various constituents of the dispensing nozzle, such as a valve support, a dispensing valve, air take-up member, filter element, filter element support, etc.
  • protein covers the following proteins or polypeptides: protein hormones, growth factors, cytokines, especially interleukins and interferons, chemokines, proteins of blood plasma, in particular albumin in the form of proteins. its different forms, coagulation factors or thrombosis, immunoglobulins, vaccine antigens from bacteria or viruses or parasites, extracellular matrix proteins, including collagen, elastin or others.
  • protein hormones protein hormones, growth factors, cytokines, especially interleukins and interferons, chemokines, proteins of blood plasma, in particular albumin in the form of proteins. its different forms, coagulation factors or thrombosis, immunoglobulins, vaccine antigens from bacteria or viruses or parasites, extracellular matrix proteins, including collagen, elastin or others.
  • cytokines especially interleukins and interferons
  • chemokines proteins of blood plasma
  • albumin in the form of proteins. its different forms, coagulation factors or thrombosis, immunoglobul
  • the object of the invention is to propose a device for storing and dispensing pharmaceutical liquids that makes it possible to guarantee the active ingredient content of the solution for a given time interval, without having to adapt the composition of the solution to the various materials of the device. .
  • the subject of the invention is a device for the storage and dispensing of pharmaceutical liquid comprising, on at least part of a surface internal device, a coating reducing the sorption of at least one of the species present in the liquid on the coated surface characterized in that the coating is hydrophobic.
  • the species present in the liquid is meant an active principle or any other species present in the solution which could, by modifying the equilibrium of the solution, promote the sorption of the active ingredient on the coated surface.
  • the species are chosen from a protein, a prostaglandin or a prostaglandin derivative.
  • sorption is meant the phenomena, combined or not, of absorption and adsorption of a molecule in or on a surface.
  • the elements of the device are generally made of thermoplastic polymer materials such as polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyoxymethylene (POM), polyarylate (PAr), polyetherketone (PEK) fluorinated polymers (for example: polyvinylidene fluoride (PVDF), cycloolefinic polymers (COC) (for example the polymers sold under the trademark "TOPAS”), cycloolefinic copolymers (COP) (for example the copolymers sold under the trademark " Zeonex "), polytetrafluoroethylene (PTFE), polychlorotrifluoroethylene (PCTFE), polysulfone (PSU), ethylene-propylene-diene monomer (EPDM), or thermosetting type such as synthetic rubbers (for example: halobutyl rubber, nitrile rubber, polyisoprenes, and polychloroprene) or else
  • These devices may also comprise polysiloxane, such as, for example, polydimethylsiloxane (PDMS) and polydimethylvinylsiloxane.
  • PDMS polydimethylsiloxane
  • PVS polydimethylvinylsiloxane
  • the materials of the device are chosen from PE, PP, PET, PBT, COP and PDMS, alone or in mixtures.
  • the different elements of the device may be of different types of materials.
  • the reservoir may be PE, the PDMS air permeable member and the chlorobutyl rubber valve. It will be understood that these elements of the device may comprise one or more of the materials listed above, taken alone or in a mixture. "Mixed” also refers to the copolymers of these materials.
  • internal surface of the device each surface that can be in contact with the liquid to be dispensed before the latter is expelled out of the device through the liquid dispensing orifice carried by the dispensing nozzle.
  • coating reducing the sorption of the liquid on the coated surface a coating which significantly reduces the sorption of the active ingredient on the surface of the device carrying the coating that is to say a coating that reduces the sorption of minus 10% relative to an untreated surface, preferably at least 20%, more preferably at least 30%, more preferably at least 50%.
  • a device which makes it possible to guarantee the stability of the solution, in particular of an ophthalmic solution comprising prostaglandins, prostaglandin analogs or proteins, in that the active ingredient remains in solution. solution within a defined concentration range and for a given time interval.
  • the quantity of active ingredient delivered is indeed that required.
  • the coating is selected from the group consisting of fluorinated molecules.
  • the coating is chosen from groups consisting of fluorinated polymers of type or derivatives of polyethylene, phosphazene, silane and paraxylylene type molecules. More preferably, the coating is chosen from poly (bis (2,2,2-trifluoroethoxy) phosphazene) (PTFEP), perfluorodecyltrichlorosilane and poly (metafluoroparaxylylene).
  • the coating may be chosen from the group consisting of silicones and their derivatives, in particular in order to create a strong bond between the coating and the material of the coated surface to ensure that the coating adheres well. More particularly, the coating is chosen from fluorinated silicones such as fluorovinylmethyl silicones (FVMQ), phenylvinylmethyl silicones (PVMQ) or PDMS.
  • FVMQ fluorovinylmethyl silicones
  • PVMQ phenylvinylmethyl silicones
  • PDMS PDMS
  • the coating may be chosen from the group consisting of poly (paraxylylene) polymers, preferably from poly (chloroparaxylylene) polymers. More preferably, the coating may be chosen from poly (paraxylylene), poly (metachloroparaxylylene), poly (metadichloroparaxylylene) or poly (metafluoroparaxylylene).
  • the coating may be chosen from the group consisting of hydrophobically modified polyethylene glycol molecules or hydrophobically modified hydroxyethylcellulose molecules. More preferentially, the coating may be chosen from hydrophobically modified hydroxyethylcellulose marketed under the trademark "Natrosol Plus”.
  • the invention relates to a device for the storage and dispensing of pharmaceutical liquid comprising, on at least a part of an internal surface of the device, a coating reducing the sorption of at least one protein or a prostaglandin or a derivative of prostaglandin present in the liquid on the coated surface characterized in that the coating is hydrophobic.
  • the coating is chosen from silicones and their derivatives.
  • the device according to the invention is such that the coating is an organosilicone, especially chosen from polydimethylsiloxane, fluorovinylmethylsilicones or phenylvinylmethyl silicones.
  • the coating is selected from the group consisting of fluorinated molecules.
  • the coating of the device of the invention may be chosen from poly (bis (2,2,2-trifluoroethoxy) phosphazene), poly (metafluoroparaxylylene), polytetrafluoroethylene, perfluorodecyltrichlorosilane or fluorovinylmethylsilicones.
  • the coating is chosen from the group consisting of poly (paraxylylene) polymers, especially chosen from poly (paraxylylene), poly (metachloroparaxylylene), poly (metadichloroparaxylylene) or poly (metafluoroparaxylylene).
  • the coating is chosen from the group consisting of hydrophobically modified polyethylene glycol molecules or hydrophobically modified hydroxyethylcellulose molecules.
  • the invention also relates to the use of a coating described above, for reducing the sorption of at least one protein, at least one prostaglandin or at least one prostaglandin analogue to an internal surface of a device.
  • the coating may comprise or be constituted by a or more than one of all the molecules listed above for coating, alone or as a mixture. By “in a mixture”, the copolymers of these molecules are also targeted. It should also be noted that the molecules listed above for the coating may be mixed with polytetrafluoroethylene (PTFE).
  • PTFE polytetrafluoroethylene
  • the device may include the coating over the entire inner surface or a portion of the inner surface.
  • the coated portion of the inner surface depends on the nature of the material composing the various elements and / or the punctual or permanent nature of the contacting of said element with the liquid or the solution.
  • the portion of the inner surface coated by the coating is an air permeable member, a reservoir and / or any surface that may be in prolonged contact with the solution.
  • prolonged contact is meant contact greater than 6 months.
  • the invention also relates to a method of manufacturing a device according to the invention, wherein the coating is applied to at least a portion of the inner surface of the device.
  • the inner surface or the inner surface portion is pretreated by plasma treatment, by corona treatment; by flaming (treatment consisting in exposing the surface of a polymeric material to an oxidizing flame) or by treatment by the method known as "Pyrosil".
  • the invention finally relates to the use of a coating chosen from the group of fluorinated molecules, silicones and their derivatives, poly (paraxylylene) polymers, hydrophobically modified polyethylene glycol molecules or hydrophobically modified hydroxyethylcellulose molecules. to reduce the sorption as defined above.
  • the coating is used to reduce the sorption of at least one prostaglandin or at least one prostaglandin analogue.
  • the coating is used to reduce the sorption of at least one protein.
  • a coating of poly (bis (2,2,2-trifluoroethoxy) phosphazene) is deposited on the inner surface of a air permeable member to ensure that the air entering the device to replace the amount of liquid delivered is free of bacteria and / or particles.
  • the inner surface of the air permeable member is activated by plasma treatment with a power of 200 W with a flow rate of dinitrogen (N 2 ) of 10 sccm ("standard cubic centimeters per minute") for about 5 minutes .
  • a 1% solution of PTFEP in ethyl acetate is made. This solution is applied to the activated inner surface of the organ to form a continuous film.
  • the organ and the liquid film are then dried in an oven at 50 ° C for 24 hours to obtain an air permeable member whose inner surface comprises a PTFEP coating.
  • Example 2 Device Containing a Polv Coating (Paraxylylene)
  • a poly (paraxylylene) coating may also be deposited on the inner surface to be treated by gas phase polymerization.
  • a precursor such as [2,2] paracyclophane which is in a pulverulent solid form is used. This principle of deposition is broken down into three stages.
  • the solid paracyclophane is heated at a temperature above 100 ° C. to sublimate
  • the paracyclophane vapors pass into a pyrolysis zone where the temperature is higher than 500 ° C., which allows the rupture of the two aliphatic C-C bonds and the formation of two reactive paraxylylene molecules,
  • the paraxylylene molecules adsorb on the surfaces and polymerize spontaneously forming the poly (paraxylylene) film.
  • the thickness of the deposited film depends on the total coated surface as well as the amount of sublimed paracyclophane.
  • Example 3 Device comprising a fluorinated silicone coating (FVMQ).
  • FVMQ fluorinated silicone coating
  • the internal surface of the air-permeable member is activated by a plasma treatment with a power of 200 W with a flow rate of nitrogen (N 2 ) of 10 sccm ("Standard cubic centimeters per minute") for about 5 minutes.
  • N 2 flow rate of nitrogen
  • a 5% solution of FVMQ solution in ethyl acetate (for example a solution sold under the trademark Nusil MED10-6655 diluted 1/12 in ethyl acetate) is prepared. This solution is applied to the activated inner surface of the organ to form a continuous film.
  • the organ and the liquid film are then dried in an oven at 50 ° C for 24 hours to obtain an air permeable member whose surface comprises a FVMQ coating.
  • Example 4 Device comprising a phenyl silicone coating (PVMQ).
  • PVMQ phenyl silicone coating
  • the inner surface of the air permeable member is activated by plasma treatment with a power of 200 W with a flow rate of dinitrogen (N 2 ) of 10 sccm ("standard cubic centimeters per minute") for about 5 minutes .
  • N 2 dinitrogen
  • a 5% solution of PVMQ solution in hexane (for example a solution marketed under the trade name Nusil CV-1152 RTV) is produced. This solution is applied to the activated inner surface of the organ to form a continuous film.
  • the organ and the liquid film are then dried in an oven at 50 ° C for 24 hours to obtain an air permeable member whose surface comprises a PVMQ coating.
  • Example 5 Device Containing a Fluorosilane Coating: Perfluorodecyltrichlorosilane
  • the surface of the air permeable member is activated by a cold plasma treatment.
  • the cold plasma surface treatment is carried out in MVD type deposition equipment: the plasma is generated using an HF generator (200 Watt, 450 sccm) in a chamber whose diameter is compatible with plates Silicon diameter 200 mm. Under these conditions, the heating induced by the surface reactions remaining very low, the physical properties of the material are retained.
  • the plasma generated from 0 2 gaseous breaks the chemical bonds of the PDMS and form the hydroxyl groups that make the surface hydrophilic.
  • This treatment easy to implement and to introduce into a production line, not only induces a surface modification as such, but also intervenes as surface pre-modification before the covalent grafting of molecules chosen a priori to avoid the non-specific adsorption phenomenon.
  • a silicon oxide Si0 2 deposit is deposited (in a SiCI 4 atmosphere) to create a hooked layer in order to improve the silane grafting which will follow.
  • a covalent grafting of (1 H, 1 H, 2 H, 2 H) -perfluorodecyltrichlorosilane is carried out in the gas phase.

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  • Organic Chemistry (AREA)
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Abstract

The present invention relates to a device for storing and dispensing pharmaceutical liquid, such as ophthalmic liquid. More particularly, the ophthalmic liquid comprises, as active principle, at least one prostaglandin, at least one analogue of a prostaglandin or at least one protein, especially for the treatment of glaucoma. The device according to the invention comprises, on at least one part of an inner surface of the device, a coating that reduces the sorption of liquid on the coated surface, this coating being hydrophobic.

Description

Dispositif de stockage et de distribution de liquide  Liquid storage and dispensing device

La présente invention concerne un dispositif de stockage et de distribution de liquide pharmaceutique tel que du liquide ophtalmique. Plus particuliÚrement, le liquide ophtalmique comprend, en tant que principe actif, au moins une prostaglandine ou un analogue de prostaglandine, notamment pour le traitement du glaucome. The present invention relates to a device for storing and dispensing pharmaceutical liquid such as ophthalmic liquid. More particularly, the ophthalmic liquid comprises, as active principle, at least one prostaglandin or a prostaglandin analogue, especially for the treatment of glaucoma.

Les prostaglandines ou analogues de prostaglandines sont des principes actifs bien connus, gĂ©nĂ©ralement administrĂ©s Ă  l'homme ou Ă  l'animal par voie topique sous forme de collyre pour le traitement du glaucome. Ces principes actifs peuvent ĂȘtre Ă©galement utilisĂ©s en association avec un deuxiĂšme agent anti-glaucomateux tel que par exemple, un bĂ©ta-bloquant, un inhibiteur de l'anhydrase carbonique ou encore un agoniste alpha-adrĂ©nergique.  Prostaglandins or prostaglandin analogues are well known active ingredients, generally administered to humans or animals topically in the form of eye drops for the treatment of glaucoma. These active ingredients can also be used in combination with a second anti-glaucoma agent such as, for example, a beta-blocker, a carbonic anhydrase inhibitor or an alpha-adrenergic agonist.

La majoritĂ© des prostaglandines ou analogues de prostaglandine n'Ă©tant pas solubles dans l'eau, leur mise en solution lors de la prĂ©paration d'un collyre prĂ©sente quelques difficultĂ©s. En effet, il est nĂ©cessaire de passer par une Ă©tape prĂ©alable de solubilisation du principe actif pour obtenir une solution aqueuse prĂȘte Ă  ĂȘtre distribuĂ©e.  The majority of prostaglandins or prostaglandin analogues are not soluble in water, their dissolution in the preparation of eye drops presents some difficulties. Indeed, it is necessary to go through a preliminary step of solubilization of the active ingredient to obtain an aqueous solution ready to be distributed.

Par ailleurs, afin de garantir la stérilité de la solution aprÚs l'ouverture du dispositif, un agent conservateur anti-microbien était souvent ajouté. Or, ces agents conservateurs, qui pouvaient contribuer à la solubilisation du principe actif et sa stabilisation au sein de la solution, sont désormais déconseillés car ils peuvent s'avérer toxiques et poser des problÚmes de tolérance, surtout dans le cadre d'un traitement de longue durée tel que le traitement d'un glaucome. La solubilisation du principe actif et sa stabilité dans le dispositif est donc susceptible de s'en trouver affectées.  Moreover, in order to guarantee the sterility of the solution after the opening of the device, an anti-microbial preservative was often added. However, these preservatives, which could contribute to the solubilization of the active ingredient and its stabilization within the solution, are now deprecated because they can be toxic and pose problems of tolerance, especially in the context of a treatment of long-term such as the treatment of glaucoma. The solubilization of the active ingredient and its stability in the device is therefore likely to be affected.

Enfin, la solution comprenant le principe actif doit ĂȘtre Ă©galement stable dans le temps. En effet, le liquide peut ĂȘtre stockĂ© jusqu'Ă  trente-six mois dans le dispositif avant sa premiĂšre ouverture, puis environ 1 mois aprĂšs sa premiĂšre ouverture, par exemple pour une administration au rythme d'une goutte dans chaque Ɠil par jour. Or on constate, au cours du temps, une rĂ©duction de la concentration en principe actif dans les gouttes dĂ©livrĂ©es. Cette rĂ©duction de concentration peut ĂȘtre due Ă  des phĂ©nomĂšnes d'absorption du principe actif dans les parties du dispositif en contact avec la solution et/ou des phĂ©nomĂšnes d'adsorption sur ces mĂȘmes parties. Elle peut Ă©galement ĂȘtre due Ă  l'absorption ou l'adsorption de toute autre espĂšce prĂ©sente dans la solution qui pourrait, par modification de l'Ă©quilibre de la solution, favoriser l'adsorption ou l'absorption du principe actif par des parties du dispositif en contact avec la solution. Ces phĂ©nomĂšnes sont particuliĂšrement critiques Ă  faible concentration car ils ne permettent pas de garantir la dĂ©livrance de la quantitĂ© requise du principe actif au cours du temps. En effet, si le principe actif rĂ©agit, de façon rĂ©versible ou non, avec l'un des matĂ©riaux des composants du dispositif lorsqu'ils sont en contact, sa concentration dans la solution diminue et peut devenir trop faible pour avoir un effet thĂ©rapeutique optimal. Or, par exemple, les prostaglandines ou analogues de prostaglandines sont gĂ©nĂ©ralement introduites dans la solution Ă  de faibles concentrations, telle qu'une concentration infĂ©rieure Ă  1 % en poids, voire infĂ©rieure Ă  0,01 % en poids. Finally, the solution comprising the active ingredient must also be stable over time. Indeed, the liquid can be stored for up to thirty-six months in the device before its first opening, then about 1 month after its first opening, for example for administration at the rate of one drop in each eye per day. However, over time, a reduction in the concentration of active ingredient in the drops delivered is observed. This reduction in concentration may be due to absorption phenomena of the active ingredient in the parts of the device in contact with the solution and / or adsorption phenomena on these same parts. It may also be due to the absorption or adsorption of any other species present in the solution which could, by modifying the equilibrium of the solution, promote the adsorption or absorption of the active ingredient by parts of the solution. device in contact with the solution. These phenomena are particularly critical at low concentrations because they do not ensure the delivery of the required amount of the active ingredient over time. Indeed, if the active ingredient reacts, reversibly or not, with one of the component materials of the device when in contact, its concentration in the solution decreases and may become too low to have an optimal therapeutic effect. However, for example, prostaglandins or prostaglandin analogues are generally introduced into the solution at low concentrations, such as a concentration of less than 1% by weight, or even less than 0.01% by weight.

Une solution Ă  ce problĂšme consiste Ă  modifier la formulation de la solution afin de rendre la solution stable et inerte vis-Ă -vis du matĂ©riau du dispositif de stockage et de distribution et ce, mĂȘme Ă  faibles concentrations. Cependant, il est frĂ©quent qu'un dispositif pour la distribution de produit avec ou sans conservateur puisse par exemple comprendre des matĂ©riaux polymĂšres diffĂ©rents pour le rĂ©servoir et pour les diffĂ©rents constituants de l'embout de distribution, tels qu'un support de valve, une valve de distribution, un organe de reprise d'air, un Ă©lĂ©ment filtrant, un support d'Ă©lĂ©ment filtrant, etc.  One solution to this problem is to modify the formulation of the solution in order to make the solution stable and inert with respect to the material of the storage and dispensing device, even at low concentrations. However, it is common for a device for dispensing product with or without a preservative, for example, to comprise different polymer materials for the reservoir and for the various constituents of the dispensing nozzle, such as a valve support, a dispensing valve, air take-up member, filter element, filter element support, etc.

Il est donc difficile d'adapter la formulation de la solution à tous les matériaux polymÚres du dispositif en contact avec la solution.  It is therefore difficult to adapt the formulation of the solution to all the polymeric materials of the device in contact with the solution.

Des problÚmes analogues de sorption des protéines se posent également lorsque l'on utilise des protéines en tant que principe actif en faibles concentrations pour d'autres utilisations thérapeutiques ou non.  Similar problems of protein sorption also arise when using proteins as an active ingredient in low concentrations for other therapeutic uses or not.

Dans l'invention, le terme « protĂ©ine » couvre les protĂ©ines ou polypeptides suivants : les hormones protĂ©iques, les facteurs de croissances, les cytokines, notamment les interleukines et les interfĂ©rons, les chimiokines, les protĂ©ines du plasma sanguin, notamment l'albumine sous ses diffĂ©rentes formes, les facteurs de coagulation ou de thrombose, les immunoglobulines, les antigĂšnes vaccinaux issus de bactĂ©ries ou de virus ou de parasites, des protĂ©ines de la matrice extracellulaire, notamment le collagĂšne, l'Ă©lastine ou autres. La prĂ©cĂ©dente liste n'a pas de caractĂšre limitatif, et l'homme de mĂ©tier du domaine de l'invention est capable de dĂ©terminer les protĂ©ines d'intĂ©rĂȘt.  In the invention, the term "protein" covers the following proteins or polypeptides: protein hormones, growth factors, cytokines, especially interleukins and interferons, chemokines, proteins of blood plasma, in particular albumin in the form of proteins. its different forms, coagulation factors or thrombosis, immunoglobulins, vaccine antigens from bacteria or viruses or parasites, extracellular matrix proteins, including collagen, elastin or others. The previous list is not limiting in nature, and one skilled in the field of the invention is capable of determining the proteins of interest.

L'invention a pour but de proposer un dispositif de stockage et de distribution de liquide pharmaceutique permettant de garantir la teneur en principe actif de la solution pendant un intervalle donné de temps, sans avoir à adapter la composition de la solution aux différents matériaux du dispositif.  The object of the invention is to propose a device for storing and dispensing pharmaceutical liquids that makes it possible to guarantee the active ingredient content of the solution for a given time interval, without having to adapt the composition of the solution to the various materials of the device. .

A cet effet, l'invention a pour objet un dispositif pour le stockage et la distribution de liquide pharmaceutique comprenant, sur au moins une partie d'une surface interne du dispositif, un revĂȘtement rĂ©duisant la sorption d'au moins l'une des espĂšces prĂ©sentes dans le liquide sur la surface revĂȘtue caractĂ©risĂ© en ce que le revĂȘtement est hydrophobe. For this purpose, the subject of the invention is a device for the storage and dispensing of pharmaceutical liquid comprising, on at least part of a surface internal device, a coating reducing the sorption of at least one of the species present in the liquid on the coated surface characterized in that the coating is hydrophobic.

Par « au moins une des espĂšces prĂ©sentes dans le liquide », on entend un principe actif ou toute autre espĂšce prĂ©sente dans la solution qui pourrait, par modification de l'Ă©quilibre de la solution, favoriser la sorption du principe actif sur la surface revĂȘtue. Avantageusement, les espĂšces sont choisies parmi une protĂ©ine, une prostaglandine ou un dĂ©rivĂ© de prostaglandine.  By "at least one of the species present in the liquid" is meant an active principle or any other species present in the solution which could, by modifying the equilibrium of the solution, promote the sorption of the active ingredient on the coated surface. Advantageously, the species are chosen from a protein, a prostaglandin or a prostaglandin derivative.

Par « sorption », on désigne les phénomÚnes, combinés ou non, d'absorption et d'adsorption d'une molécule dans ou sur une surface.  By "sorption" is meant the phenomena, combined or not, of absorption and adsorption of a molecule in or on a surface.

On entend par « dispositif de stockage et de distribution », un dispositif comprenant un rĂ©servoir de stockage du liquide Ă  distribuer et un embout de distribution du produit. Ces dispositifs peuvent par exemple ĂȘtre destinĂ©s Ă  la distribution de gouttes et comporter une valve de distribution de liquide et/ou un organe permĂ©able Ă  l'air. Ces dispositifs peuvent Ă©galement ĂȘtre destinĂ©s Ă  l'injection de liquide, par exemple sous forme d'une seringue munie d'une aiguille d'injection.  The term "storage and distribution device", a device comprising a storage tank of the liquid to be dispensed and a product dispensing tip. These devices may for example be intended for dispensing drops and comprise a liquid distribution valve and / or an air permeable member. These devices may also be intended for the injection of liquid, for example in the form of a syringe provided with an injection needle.

Les éléments du dispositif sont généralement en matériaux polymÚres du type thermoplastique comme polyéthylÚne (PE), polypropylÚne (PP), polyéthylÚne- téréphtalate (PET), polybutylÚne théréphtalate (PBT), polyoxyméthylÚne (POM), polyarylate (PAr), polyéthercétone (PEK), polymÚres fluorés (par exemple : polyfluorure de vinylidÚne (PVDF), polymÚres cyclo-oléfiniques (COC) (par exemple les polymÚres commercialisés sous la marque « TOPAS »), copolymÚres cyclooléfiniques (COP) (par exemple les copolymÚres commercialisés sous la marque « Zeonex »), polytétrafluoroéthylÚne (PTFE), polychlorotrifluoroéthylÚne (PCTFE)), polysulfone (PSU), éthylÚne-propylÚne-diÚne monomÚre (EPDM), ou de type thermodurcissable comme les caoutchoucs synthétiques (par exemple: les caoutchouc halogénobutyles, les caoutchoucs nitriles, les polyisoprÚnes, et les polychloroprÚne) ou encore du type élastomÚres thermoplastiques (par exemple : copolymÚre EPDM-PP commercialisé sous la marque « SantoprÚne », copolymÚre bloc styrÚne-éthylÚne-butylÚne-styrÚne (SEBS), etc.), seuls ou en mélanges. Ces dispositifs peuvent également comprendre du polysiloxane, comme par exemple du polydiméthylsiloxane (PDMS) et du polydimethylvinylsiloxane.  The elements of the device are generally made of thermoplastic polymer materials such as polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyoxymethylene (POM), polyarylate (PAr), polyetherketone (PEK) fluorinated polymers (for example: polyvinylidene fluoride (PVDF), cycloolefinic polymers (COC) (for example the polymers sold under the trademark "TOPAS"), cycloolefinic copolymers (COP) (for example the copolymers sold under the trademark " Zeonex "), polytetrafluoroethylene (PTFE), polychlorotrifluoroethylene (PCTFE), polysulfone (PSU), ethylene-propylene-diene monomer (EPDM), or thermosetting type such as synthetic rubbers (for example: halobutyl rubber, nitrile rubber, polyisoprenes, and polychloroprene) or else of the thermoplastic elastomer type (for example: commercial EPDM-PP copolymer). under the trademark "Santoprene", styrene-ethylene-butylene-styrene block copolymer (SEBS), etc.), alone or in mixtures. These devices may also comprise polysiloxane, such as, for example, polydimethylsiloxane (PDMS) and polydimethylvinylsiloxane.

PrĂ©fĂ©rentiellement, les matĂ©riaux du dispositif sont choisis parmi le PE, le PP, le PET, le PBT, le COP et le PDMS, seuls ou en mĂ©langes. Les diffĂ©rents Ă©lĂ©ments du dispositif peuvent ĂȘtre en matĂ©riaux de types diffĂ©rents. Ainsi, le rĂ©servoir peut ĂȘtre en PE, l'organe permĂ©able Ă  l'air en PDMS et la valve en caoutchouc chlorobutyle. On comprendra que ces Ă©lĂ©ments du dispositif peuvent comprendre l'un ou plusieurs des matĂ©riaux listĂ©s ci-dessus, pris seuls ou en mĂ©lange. Par « en mĂ©lange », on vise Ă©galement les copolymĂšres de ces matĂ©riaux. Preferably, the materials of the device are chosen from PE, PP, PET, PBT, COP and PDMS, alone or in mixtures. The different elements of the device may be of different types of materials. Thus, the reservoir may be PE, the PDMS air permeable member and the chlorobutyl rubber valve. It will be understood that these elements of the device may comprise one or more of the materials listed above, taken alone or in a mixture. "Mixed" also refers to the copolymers of these materials.

On entend par « surface interne » du dispositif chaque surface qui peut ĂȘtre en contact avec le liquide Ă  distribuer avant que ce dernier ne soit expulsĂ© hors du dispositif par l'orifice de distribution du liquide portĂ© par l'embout de distribution. The term "internal surface" of the device each surface that can be in contact with the liquid to be dispensed before the latter is expelled out of the device through the liquid dispensing orifice carried by the dispensing nozzle.

On entend par « revĂȘtement rĂ©duisant la sorption du liquide sur la surface revĂȘtue », un revĂȘtement qui rĂ©duit notablement la sorption du principe actif sur la surface du dispositif portant le revĂȘtement c'est-Ă -dire un revĂȘtement qui rĂ©duit la sorption d'au moins 10% par rapport Ă  une surface non traitĂ©e, de prĂ©fĂ©rence d'au moins 20%, plus prĂ©fĂ©rentiellement d'au moins 30%, plus prĂ©fĂ©rentiellement encore d'au moins 50%. The term "coating reducing the sorption of the liquid on the coated surface", a coating which significantly reduces the sorption of the active ingredient on the surface of the device carrying the coating that is to say a coating that reduces the sorption of minus 10% relative to an untreated surface, preferably at least 20%, more preferably at least 30%, more preferably at least 50%.

Ainsi, grùce à l'invention, on obtient un dispositif qui permet de garantir la stabilité de la solution, en particulier d'une solution ophtalmique comportant des prostaglandines, des analogues de prostaglandine ou des protéines, en ce sens que le principe actif reste en solution dans une gamme de concentration définie et pendant un intervalle de temps donné. Ainsi, à chaque délivrance d'une goutte de produit, la quantité de principe actif délivré est bien celle requise.  Thus, thanks to the invention, a device is obtained which makes it possible to guarantee the stability of the solution, in particular of an ophthalmic solution comprising prostaglandins, prostaglandin analogs or proteins, in that the active ingredient remains in solution. solution within a defined concentration range and for a given time interval. Thus, with each delivery of a drop of product, the quantity of active ingredient delivered is indeed that required.

En outre, comme la sorption est trÚs limitée, voire nulle, il n'est plus nécessaire de stocker le dispositif dans un réfrigérateur avant ou pendant utilisation.  In addition, since the sorption is very limited, or even zero, it is no longer necessary to store the device in a refrigerator before or during use.

Selon un premier mode de rĂ©alisation, le revĂȘtement est choisi parmi le groupe constituĂ© par les molĂ©cules fluorĂ©es. De prĂ©fĂ©rence, le revĂȘtement est choisi parmi les groupes constituĂ©s par les polymĂšres fluorĂ©s de type ou dĂ©rivĂ©s de molĂ©cules de type polyĂ©thylĂšne, phosphazĂšne, silane et paraxylylĂšne. De maniĂšre plus prĂ©fĂ©rentielle, le revĂȘtement est choisi parmi le poly(bis(2,2,2- trifluoroĂ©thoxy)phosphazĂšne) (PTFEP), le perfluorodecyltrichlorosilane, le poly(mĂ©tafluoroparaxylylĂšne).  According to a first embodiment, the coating is selected from the group consisting of fluorinated molecules. Preferably, the coating is chosen from groups consisting of fluorinated polymers of type or derivatives of polyethylene, phosphazene, silane and paraxylylene type molecules. More preferably, the coating is chosen from poly (bis (2,2,2-trifluoroethoxy) phosphazene) (PTFEP), perfluorodecyltrichlorosilane and poly (metafluoroparaxylylene).

Selon un second mode de rĂ©alisation, le revĂȘtement peut ĂȘtre choisi parmi le groupe constituĂ© par les silicones et leurs dĂ©rivĂ©s afin notamment de crĂ©er une liaison forte entre le revĂȘtement et le matĂ©riau de la surface revĂȘtue pour garantir le bon accrochage du revĂȘtement. Plus particuliĂšrement, le revĂȘtement est choisi parmi les silicones fluorĂ©s tels que les fluorovinylmĂ©thyl silicones (FVMQ), les phĂ©nylvinylmĂ©thyl silicones (PVMQ) ou le PDMS.  According to a second embodiment, the coating may be chosen from the group consisting of silicones and their derivatives, in particular in order to create a strong bond between the coating and the material of the coated surface to ensure that the coating adheres well. More particularly, the coating is chosen from fluorinated silicones such as fluorovinylmethyl silicones (FVMQ), phenylvinylmethyl silicones (PVMQ) or PDMS.

Selon un troisiĂšme mode de rĂ©alisation, le revĂȘtement peut ĂȘtre choisi parmi le groupe constituĂ© par les polymĂšres de poly(paraxylylĂšne), de prĂ©fĂ©rence, parmi les polymĂšres de poly(chloroparaxylylĂšne). De maniĂšre plus prĂ©fĂ©rentielle, le revĂȘtement peut ĂȘtre choisi parmi le poly(paraxylylĂšne), le poly(mĂ©tachloroparaxylylĂšne), le poly(mĂ©tadichloroparaxylylĂšne) ou le poly(mĂ©tafluoroparaxylylĂšne). According to a third embodiment, the coating may be chosen from the group consisting of poly (paraxylylene) polymers, preferably from poly (chloroparaxylylene) polymers. More preferably, the coating may be chosen from poly (paraxylylene), poly (metachloroparaxylylene), poly (metadichloroparaxylylene) or poly (metafluoroparaxylylene).

Selon un quatriĂšme mode de rĂ©alisation, le revĂȘtement peut ĂȘtre choisi parmi le groupe constituĂ© par les molĂ©cules de polyĂ©thylĂšne glycol modifiĂ©es hydrophobiquement ou les molĂ©cules d'hydroxyĂ©thylcellulose modifiĂ©e hydrophobiquement. Plus prĂ©fĂ©rentiellement, le revĂȘtement peut ĂȘtre choisi parmi l'hydroxyĂ©thylcellulose modifiĂ©e hydrophobiquement commercialisĂ©e sous la marque « Natrosol Plus ».  According to a fourth embodiment, the coating may be chosen from the group consisting of hydrophobically modified polyethylene glycol molecules or hydrophobically modified hydroxyethylcellulose molecules. More preferentially, the coating may be chosen from hydrophobically modified hydroxyethylcellulose marketed under the trademark "Natrosol Plus".

Avantageusement, l'invention concerne un dispositif pour le stockage et la distribution de liquide pharmaceutique comprenant, sur au moins une partie d'une surface interne du dispositif, un revĂȘtement rĂ©duisant la sorption d'au-moins une protĂ©ine ou une prostaglandine ou un dĂ©rivĂ© de prostaglandine prĂ©sents dans le liquide sur la surface revĂȘtue caractĂ©risĂ© en ce que le revĂȘtement est hydrophobe.  Advantageously, the invention relates to a device for the storage and dispensing of pharmaceutical liquid comprising, on at least a part of an internal surface of the device, a coating reducing the sorption of at least one protein or a prostaglandin or a derivative of prostaglandin present in the liquid on the coated surface characterized in that the coating is hydrophobic.

Dans un mode rĂ©alisation avantageux, le revĂȘtement est choisi parmi les silicones et leurs dĂ©rivĂ©s.  In an advantageous embodiment, the coating is chosen from silicones and their derivatives.

Le dispositif selon l'invention est tel que le revĂȘtement est un organosiliconĂ©, notamment choisi parmi le polydimĂ©thylsiloxane, les fluorovinylmĂ©thylsilicones ou les phĂ©nylvinylmĂ©thyl silicones.  The device according to the invention is such that the coating is an organosilicone, especially chosen from polydimethylsiloxane, fluorovinylmethylsilicones or phenylvinylmethyl silicones.

Dans un autre mode de rĂ©alisation encore plus avantageux, le revĂȘtement est choisi parmi le groupe constituĂ© par les molĂ©cules fluorĂ©es.  In another even more advantageous embodiment, the coating is selected from the group consisting of fluorinated molecules.

Le revĂȘtement du dispositif de l'invention peut ĂȘtre choisi parmi le poly(bis(2,2,2- trifluoroĂ©thoxy)phosphazĂšne), le poly(mĂ©tafluoroparaxylylĂšne), le polytĂ©trafluoroĂ©thylĂšne, le perfluorodecyltrichlorosilane ou les fluorovinylmĂ©thylsilicones.  The coating of the device of the invention may be chosen from poly (bis (2,2,2-trifluoroethoxy) phosphazene), poly (metafluoroparaxylylene), polytetrafluoroethylene, perfluorodecyltrichlorosilane or fluorovinylmethylsilicones.

Selon un autre aspect avantageux, le revĂȘtement est choisi parmi le groupe constituĂ© par les polymĂšres de poly(paraxylylĂšne), notamment choisi parmi le poly(paraxylylĂšne), le poly(mĂ©tachloroparaxylylĂšne), le poly(mĂ©tadichloroparaxylylĂšne) ou le poly(mĂ©tafluoroparaxylylĂšne).  According to another advantageous aspect, the coating is chosen from the group consisting of poly (paraxylylene) polymers, especially chosen from poly (paraxylylene), poly (metachloroparaxylylene), poly (metadichloroparaxylylene) or poly (metafluoroparaxylylene).

Selon encore un autre aspect avantageux, le revĂȘtement est choisi parmi le groupe constituĂ© par les molĂ©cules de polyĂ©thylĂšne glycol modifiĂ©es hydrophobiquement ou les molĂ©cules d'hydroxyĂ©thylcellulose modifiĂ©es hydrophobiquement.  According to yet another advantageous aspect, the coating is chosen from the group consisting of hydrophobically modified polyethylene glycol molecules or hydrophobically modified hydroxyethylcellulose molecules.

L'invention concerne Ă©galement l'utilisation d'un revĂȘtement dĂ©crit prĂ©cĂ©demment, pour rĂ©duire la sorption d'au moins une protĂ©ine, d'au moins une prostaglandine ou d'au moins un analogue d'une prostaglandine sur une surface interne d'un dispositif.  The invention also relates to the use of a coating described above, for reducing the sorption of at least one protein, at least one prostaglandin or at least one prostaglandin analogue to an internal surface of a device.

On comprendra que le revĂȘtement peut comprendre ou ĂȘtre constituĂ© par une ou plusieurs de l'ensemble de toutes les molĂ©cules listĂ©es ci-dessus pour le revĂȘtement, prises seules ou en mĂ©lange. Par « en mĂ©lange », on vise Ă©galement les copolymĂšres de ces molĂ©cules. On notera par ailleurs que les molĂ©cules listĂ©es ci-dessus pour le revĂȘtement peuvent ĂȘtre en mĂ©lange avec du polytĂ©trafluoroĂ©thylĂšne (PTFE). It will be understood that the coating may comprise or be constituted by a or more than one of all the molecules listed above for coating, alone or as a mixture. By "in a mixture", the copolymers of these molecules are also targeted. It should also be noted that the molecules listed above for the coating may be mixed with polytetrafluoroethylene (PTFE).

Le dispositif peut comporter le revĂȘtement sur l'intĂ©gralitĂ© de la surface interne ou sur une partie de la surface interne. La partie revĂȘtue de la surface interne dĂ©pend de la nature du matĂ©riau composant les diffĂ©rents Ă©lĂ©ments et/ou du caractĂšre ponctuel ou permanent de la mise en contact dudit Ă©lĂ©ment avec le liquide ou la solution. Avantageusement, la partie de la surface interne revĂȘtue par le revĂȘtement est un organe permĂ©able Ă  l'air, un rĂ©servoir et/ou toute surface pouvant ĂȘtre en contact prolongĂ© avec la solution. Par « contact prolongĂ© », on entend un contact supĂ©rieur Ă  6 mois.  The device may include the coating over the entire inner surface or a portion of the inner surface. The coated portion of the inner surface depends on the nature of the material composing the various elements and / or the punctual or permanent nature of the contacting of said element with the liquid or the solution. Advantageously, the portion of the inner surface coated by the coating is an air permeable member, a reservoir and / or any surface that may be in prolonged contact with the solution. By "prolonged contact" is meant contact greater than 6 months.

L'invention concerne Ă©galement un procĂ©dĂ© de fabrication d'un dispositif selon l'invention, dans lequel le revĂȘtement est appliquĂ© sur au moins une partie de la surface interne du dispositif.  The invention also relates to a method of manufacturing a device according to the invention, wherein the coating is applied to at least a portion of the inner surface of the device.

Avantageusement, avant de dĂ©poser le revĂȘtement, la surface interne ou la partie de surface interne est prĂ©-traitĂ©e par traitement plasma, par traitement corona ; par un flammage (traitement consistant Ă  exposer la surface d'un matĂ©riau polymĂšre Ă  une flamme oxydante) ou encore par un traitement par la mĂ©thode connue sous le nom de « Pyrosil ».  Advantageously, before depositing the coating, the inner surface or the inner surface portion is pretreated by plasma treatment, by corona treatment; by flaming (treatment consisting in exposing the surface of a polymeric material to an oxidizing flame) or by treatment by the method known as "Pyrosil".

L'invention concerne enfin l'utilisation d'un revĂȘtement choisi parmi le groupe des molĂ©cules fluorĂ©es, des silicones et de leurs dĂ©rivĂ©s, des polymĂšres de poly(paraxylylĂšne), des molĂ©cules de polyĂ©thylĂšne glycol modifiĂ©es hydrophobiquement ou des molĂ©cules d'hydroxyĂ©thylcellulose modifiĂ©es hydrophobiquement, pour rĂ©duire la sorption telle que dĂ©finie prĂ©cĂ©demment.  The invention finally relates to the use of a coating chosen from the group of fluorinated molecules, silicones and their derivatives, poly (paraxylylene) polymers, hydrophobically modified polyethylene glycol molecules or hydrophobically modified hydroxyethylcellulose molecules. to reduce the sorption as defined above.

On comprend que cette utilisation pour rĂ©duire la sorption de la prostaglandine, de l'analogue de la prostaglandine ou de la protĂ©ine peut ĂȘtre envisagĂ©e avec un revĂȘtement comprenant ou constituĂ© de l'une quelconque des molĂ©cules listĂ©es ci- dessus pour le revĂȘtement, prise seule ou en mĂ©lange les unes avec les autres.  It is understood that this use for reducing the sorption of prostaglandin, prostaglandin analogue or protein may be contemplated with a coating comprising or consisting of any of the molecules listed above for coating, taken alone. or mixed with each other.

Dans un mode de rĂ©alisation, on utilise le revĂȘtement pour rĂ©duire la sorption d'au moins une prostaglandine ou d'au moins un analogue d'une prostaglandine.  In one embodiment, the coating is used to reduce the sorption of at least one prostaglandin or at least one prostaglandin analogue.

Dans un autre mode de rĂ©alisation, on utilise le revĂȘtement pour rĂ©duire la sorption d'au moins une protĂ©ine.  In another embodiment, the coating is used to reduce the sorption of at least one protein.

Exemple 1 : Dispositif comportant un revĂȘtement en PTFEP  Example 1 Device Comprising a PTFEP Coating

Dans cet exemple, un revĂȘtement de poly(bis(2,2,2- trifluoroĂ©thoxy)phosphazĂšne) (PTFEP) est dĂ©posĂ© sur la surface interne d'un organe permĂ©able Ă  l'air permettant de s'assurer que l'air entrant dans le dispositif pour remplacer la quantitĂ© de liquide dĂ©livrĂ© est exempt de bactĂ©ries et/ou de particules. In this example, a coating of poly (bis (2,2,2-trifluoroethoxy) phosphazene) (PTFEP) is deposited on the inner surface of a air permeable member to ensure that the air entering the device to replace the amount of liquid delivered is free of bacteria and / or particles.

On rappelle que l'on entend par « surface interne » du dispositif, chaque surface qui peut ĂȘtre en contact avec le liquide Ă  distribuer avant que ce dernier ne soit expulsĂ© hors du dispositif par l'orifice de distribution du liquide portĂ© par l'embout de distribution.  It is recalled that the term "internal surface" of the device, each surface that can be in contact with the liquid to be dispensed before the latter is expelled from the device through the liquid dispensing orifice carried by the nozzle of distribution.

La surface interne de l'organe perméable à l'air est activée par un traitement plasma d'une puissance de 200 W avec un débit de diazote (N2) de 10 sccm (« standard cubic centimeters per minute ») pendant environ 5 minutes. The inner surface of the air permeable member is activated by plasma treatment with a power of 200 W with a flow rate of dinitrogen (N 2 ) of 10 sccm ("standard cubic centimeters per minute") for about 5 minutes .

On réalise une solution à 1 % de PTFEP dans de l'acétate d'éthyle. Cette solution est appliquée sur la surface interne activée de l'organe afin de former un film continu.  A 1% solution of PTFEP in ethyl acetate is made. This solution is applied to the activated inner surface of the organ to form a continuous film.

L'organe et le film liquide sont ensuite mis Ă  sĂ©cher dans une Ă©tuve Ă  50°C pendant 24h pour obtenir un organe permĂ©able Ă  l'air dont la surface interne comprend un revĂȘtement de PTFEP.  The organ and the liquid film are then dried in an oven at 50 ° C for 24 hours to obtain an air permeable member whose inner surface comprises a PTFEP coating.

Exemple 2 : Dispositif comportant un revĂȘtement en polv( paraxylylĂšne)  Example 2 Device Containing a Polv Coating (Paraxylylene)

Un revĂȘtement de poly(paraxylylĂšne) peut Ă©galement ĂȘtre dĂ©posĂ© sur la surface interne Ă  traiter par polymĂ©risation en phase gazeuse.  A poly (paraxylylene) coating may also be deposited on the inner surface to be treated by gas phase polymerization.

On utilise par exemple un précurseur tel que du [2,2]paracyclophane qui se présente sous une forme solide pulvérulente. Ce principe de déposition se décompose en trois étapes.  For example, a precursor such as [2,2] paracyclophane which is in a pulverulent solid form is used. This principle of deposition is broken down into three stages.

Sous vide primaire (~10~1 Pa) : Under primary vacuum (~ 10 ~ 1 Pa):

- le paracyclophane solide est chauffé à une température supérieure à 100°C pour se sublimer,  the solid paracyclophane is heated at a temperature above 100 ° C. to sublimate,

- les vapeurs de paracyclophane passent dans une zone de pyrolyse oĂč la tempĂ©rature est supĂ©rieure Ă  500°C ce qui permet la rupture des deux liaisons C- C aliphatiques et la formation de deux molĂ©cules de paraxylylĂšne rĂ©actives,  the paracyclophane vapors pass into a pyrolysis zone where the temperature is higher than 500 ° C., which allows the rupture of the two aliphatic C-C bonds and the formation of two reactive paraxylylene molecules,

- enfin, en pénétrant dans la chambre de déposition à température ambiante, les molécules de paraxylylÚne s'adsorbent sur les surfaces et polymérisent spontanément formant le film de poly(paraxylylÚne).  Finally, by penetrating into the deposition chamber at room temperature, the paraxylylene molecules adsorb on the surfaces and polymerize spontaneously forming the poly (paraxylylene) film.

L'Ă©paisseur du film dĂ©posĂ© dĂ©pend de la surface totale revĂȘtue ainsi que de la quantitĂ© de paracyclophane sublimĂ©e.  The thickness of the deposited film depends on the total coated surface as well as the amount of sublimed paracyclophane.

Exemple 3 : Dispositif comportant un revĂȘtement en silicone fluorĂ© (FVMQ). La surface interne de l'organe permĂ©able Ă  l'air est activĂ©e par un traitement plasma d'une puissance de 200 W avec un dĂ©bit de diazote (N2) de 10 sccm (« standard cubic centimeters per minute ») pendant environ 5 minutes. Example 3: Device comprising a fluorinated silicone coating (FVMQ). The internal surface of the air-permeable member is activated by a plasma treatment with a power of 200 W with a flow rate of nitrogen (N 2 ) of 10 sccm ("Standard cubic centimeters per minute") for about 5 minutes.

On réalise une solution à 5% de solution de FVMQ dans de l'acétate d'éthyle (par exemple une solution commercialisée sous la marque Nusil MED10-6655 diluée au 1/12 dans l'acétate d'éthyle). Cette solution est appliquée sur la surface interne activée de l'organe afin de former un film continu.  A 5% solution of FVMQ solution in ethyl acetate (for example a solution sold under the trademark Nusil MED10-6655 diluted 1/12 in ethyl acetate) is prepared. This solution is applied to the activated inner surface of the organ to form a continuous film.

L'organe et le film liquide sont ensuite mis Ă  sĂ©cher dans une Ă©tuve Ă  50°C pendant 24h pour obtenir un organe permĂ©able Ă  l'air dont la surface comprend un revĂȘtement de FVMQ.  The organ and the liquid film are then dried in an oven at 50 ° C for 24 hours to obtain an air permeable member whose surface comprises a FVMQ coating.

Exemple 4 : Dispositif comportant un revĂȘtement en silicone phĂ©nylĂ© (PVMQ). La surface interne de l'organe permĂ©able Ă  l'air est activĂ©e par un traitement plasma d'une puissance de 200 W avec un dĂ©bit de diazote (N2) de 10 sccm (« standard cubic centimeters per minute ») pendant environ 5 minutes. Example 4: Device comprising a phenyl silicone coating (PVMQ). The inner surface of the air permeable member is activated by plasma treatment with a power of 200 W with a flow rate of dinitrogen (N 2 ) of 10 sccm ("standard cubic centimeters per minute") for about 5 minutes .

On réalise une solution à 5% de solution de PVMQ dans l'hexane (par exemple une solution commercialisée sous la marque Nusil CV-1152 RTV). Cette solution est appliquée sur la surface interne activée de l'organe afin de former un film continu.  A 5% solution of PVMQ solution in hexane (for example a solution marketed under the trade name Nusil CV-1152 RTV) is produced. This solution is applied to the activated inner surface of the organ to form a continuous film.

L'organe et le film liquide sont ensuite mis Ă  sĂ©cher dans une Ă©tuve Ă  50°C pendant 24h pour obtenir un organe permĂ©able Ă  l'air dont la surface comprend un revĂȘtement de PVMQ.  The organ and the liquid film are then dried in an oven at 50 ° C for 24 hours to obtain an air permeable member whose surface comprises a PVMQ coating.

Exemple 5 : Dispositif comportant un revĂȘtement en fluorosilane : le perfluorodecyltrichlorosilane  Example 5 Device Containing a Fluorosilane Coating: Perfluorodecyltrichlorosilane

La surface de l'organe perméable à l'air est activée par un traitement plasma froid. Le traitement de surface par plasma froid est réalisé dans un équipement de dépÎt type MVD : la génération du plasma se fait à l'aide d'un générateur HF (200 Watt, 450 sccm) dans une chambre dont le diamÚtre est compatible avec des plaques de silicium de diamÚtre 200 mm. Dans ces conditions, réchauffement induit par les réactions en surface restant trÚs faible, les propriétés physiques du matériau sont conservées. Le plasma, généré à partir d'02 gazeux permet de rompre les liaisons chimiques du PDMS et de former les groupements hydroxyles qui rendent la surface hydrophile. Ce traitement, facile à mettre en oeuvre et à introduire dans une chaßne de production, induit non seulement une modification de surface en tant que telle, mais intervient aussi comme pré-modification de surface avant le greffage covalent de molécules choisies a priori pour éviter le phénomÚne d'adsorption non spécifique. The surface of the air permeable member is activated by a cold plasma treatment. The cold plasma surface treatment is carried out in MVD type deposition equipment: the plasma is generated using an HF generator (200 Watt, 450 sccm) in a chamber whose diameter is compatible with plates Silicon diameter 200 mm. Under these conditions, the heating induced by the surface reactions remaining very low, the physical properties of the material are retained. The plasma, generated from 0 2 gaseous breaks the chemical bonds of the PDMS and form the hydroxyl groups that make the surface hydrophilic. This treatment, easy to implement and to introduce into a production line, not only induces a surface modification as such, but also intervenes as surface pre-modification before the covalent grafting of molecules chosen a priori to avoid the non-specific adsorption phenomenon.

On réalise ensuite un dépÎt d'oxyde de silicium Si02 (sous atmosphÚre de SiCI4) pour créer une couche d'accroché afin d'améliorer le greffage de silane qui va suivre. Enfin on réalise un greffage covalent, en phase gazeuse, du (1 H, 1 H, 2H, 2H)- perfluorodecyltrichlorosilane. Subsequently, a silicon oxide Si0 2 deposit is deposited (in a SiCI 4 atmosphere) to create a hooked layer in order to improve the silane grafting which will follow. Finally, a covalent grafting of (1 H, 1 H, 2 H, 2 H) -perfluorodecyltrichlorosilane is carried out in the gas phase.

Claims

REVENDICATIONS 1 . Dispositif pour le stockage et la distribution de liquide pharmaceutique comprenant, sur au moins une partie d'une surface interne du dispositif, un revĂȘtement rĂ©duisant la sorption d'au-moins une protĂ©ine ou une prostaglandine ou un dĂ©rivĂ© de prostaglandine prĂ©sents dans le liquide sur la surface revĂȘtue caractĂ©risĂ© en ce que le revĂȘtement est hydrophobe. 1. Device for the storage and dispensing of pharmaceutical liquid comprising, on at least a part of an internal surface of the device, a coating reducing the sorption of at least one protein or a prostaglandin or a prostaglandin derivative present in the liquid on the coated surface characterized in that the coating is hydrophobic. 2. Dispositif selon la revendication 1 , dans lequel le revĂȘtement est choisi parmi les silicones et leurs dĂ©rivĂ©s.  2. Device according to claim 1, wherein the coating is selected from silicones and their derivatives. 3. Dispositif selon la revendication prĂ©cĂ©dente, dans lequel le revĂȘtement est un organosiliconĂ©, notamment choisi parmi le polydimĂ©thylsiloxane, les fluorovinylmĂ©thylsilicones ou les phĂ©nylvinylmĂ©thyl silicones.  3. Device according to the preceding claim, wherein the coating is an organosilicone, especially selected from polydimethylsiloxane, fluorovinylmethylsilicones or phenylvinylmethyl silicones. 4. Dispositif selon l'une quelconque des revendications 1 Ă  3, dans lequel le revĂȘtement est choisi parmi le groupe constituĂ© par les molĂ©cules fluorĂ©es.  4. Device according to any one of claims 1 to 3, wherein the coating is selected from the group consisting of fluorinated molecules. 5. Dispositif selon la revendication prĂ©cĂ©dente, dans lequel le revĂȘtement est choisi parmi le poly(bis(2,2,2-trifluoroĂ©thoxy)phosphazĂšne), le poly(mĂ©tafluoroparaxylylĂšne), le polytĂ©trafluoroĂ©thylĂšne, le perfluorodecyltrichlorosilane ou les fluorovinylmĂ©thylsilicones.  5. Device according to the preceding claim, wherein the coating is selected from poly (bis (2,2,2-trifluoroethoxy) phosphazene), poly (metafluoroparaxylylene), polytetrafluoroethylene, perfluorodecyltrichlorosilane or fluorovinylmethylsilicones. 6. Dispositif selon la revendication 1 , dans lequel le revĂȘtement est choisi parmi le groupe constituĂ© par les polymĂšres de poly(paraxylylĂšne).  The device of claim 1, wherein the coating is selected from the group consisting of poly (paraxylylene) polymers. 7. Dispositif selon la revendication prĂ©cĂ©dente, dans lequel le revĂȘtement est choisi parmi le poly(paraxylylĂšne), le poly(mĂ©tachloroparaxylylĂšne), le poly(mĂ©tadichloroparaxylylĂšne) ou le poly(mĂ©tafluoroparaxylylĂšne).  7. Device according to the preceding claim, wherein the coating is selected from poly (paraxylylene), poly (metachloroparaxylylene), poly (metadichloroparaxylylene) or poly (metafluoroparaxylylene). 8. Dispositif selon la revendication 1 , dans lequel le revĂȘtement est choisi parmi le groupe constituĂ© par les molĂ©cules de polyĂ©thylĂšne glycol modifiĂ©es hydrophobiquement ou les molĂ©cules d'hydroxyĂ©thylcellulose modifiĂ©es hydrophobiquement.  The device of claim 1, wherein the coating is selected from the group consisting of hydrophobically modified polyethylene glycol molecules or hydrophobically modified hydroxyethylcellulose molecules. 9. Dispositif selon l'une quelconque des revendications prĂ©cĂ©dentes, dans lequel la partie de la surface interne revĂȘtue par le revĂȘtement est un organe permĂ©able Ă  l'air ou un rĂ©servoir.  9. Device according to any one of the preceding claims, wherein the portion of the inner surface coated by the coating is an air permeable member or a reservoir. 10. ProcĂ©dĂ© de fabrication d'un dispositif selon l'une quelconque des revendications 1 Ă  9, dans lequel le revĂȘtement est appliquĂ© sur au moins une partie de la surface interne du dispositif.  10. A method of manufacturing a device according to any one of claims 1 to 9, wherein the coating is applied on at least a portion of the inner surface of the device. 1 1 . ProcĂ©dĂ© selon la revendication prĂ©cĂ©dente, dans lequel, avant de dĂ©poser le revĂȘtement, la partie de la surface interne est prĂ©-traitĂ©e par traitement plasma ou par traitement Corona.  1 1. Method according to the preceding claim, wherein, before depositing the coating, the portion of the inner surface is pretreated by plasma treatment or corona treatment. 12. Utilisation d'un revĂȘtement choisi parmi le groupe des silicones et de leurs dĂ©rivĂ©s, des molĂ©cules fluorĂ©es, des polymĂšres de poly(paraxylylĂšne), des molĂ©cules de polyĂ©thylĂšne glycol modifiĂ©es hydrophobiquement ou des molĂ©cules d'hydroxyĂ©thylcellulose modifiĂ©es hydrophobiquement, pour rĂ©duire la sorption d'au moins une protĂ©ine, d'au moins une prostaglandine ou d'au moins un analogue d'une prostaglandine sur une surface interne d'un dispositif. 12. Use of a coating selected from the group of silicones and their derivatives, fluorinated molecules, poly (paraxylylene) polymers, hydrophobically modified polyethylene glycol molecules or hydrophobically modified hydroxyethylcellulose molecules, for reducing the sorption of at least one protein, at least one prostaglandin or at least one prostaglandin analogue on an inner surface of a device.
PCT/FR2012/052079 2011-09-16 2012-09-17 Device for storing and dispensing liquid WO2013038119A2 (en)

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JPH05132065A (en) * 1991-11-05 1993-05-28 Nichiden Rika Glass Hanbai Kk Surface-treated glass bottle
DE19921303C1 (en) * 1999-05-07 2000-10-12 Schott Glas Medical glass container, for holding pharmaceutical or medical diagnostic solution, has an inner PECVD non-stick layer containing silicon, oxygen, carbon and hydrogen
SE0004610D0 (en) * 2000-12-13 2000-12-13 Astrazeneca Ab Surface modification process
GB0117879D0 (en) * 2001-07-21 2001-09-12 Common Services Agency Storage of liquid compositions
US7648487B2 (en) * 2004-09-28 2010-01-19 Nipro Corporation Syringe
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