Polymer suitable for forming a slippery coating for ophthalmic injectors

Abstract

The invention relates to a polymer with adjusted molar masses and hydrophilic-hydrophobic balance, suitable for forming a slip-resistant coating on the internal surface of at least one part of an intraocular implant delivery device. The invention also relates to the use of said polymer for coating the internal surface of one or more parts of an intraocular implant delivery device, the method for coating said surface, and an intraocular implant delivery device comprising at least one part whose internal surface is coated with said polymer.

Description

Description Title of the invention: Polymer capable of forming a slippery coating for ophthalmic injector technical field

[0001] The invention relates to the development of a slippery coating intended to coat the tip and / or cartridge of an intraocular implant injection device, allowing injection via micro-incision. This coating's main property is to allow the folded implant to slide along the tip and / or the cartridge without detach and without being pulled into the eye. State of the art

[0002] — The replacement of the lens of the eye affected by cataracts is ensured by Intraocular implants. Surgery using phacoemulsification allows for the removal of... destruction of the natural lens and its removal through a small incision. It was developed implants made of flexible and pliable materials that can be inserted using of injection devices through the micro-incision made for phacoemulsification fication.

[0003] — The injection system consists of a tubular body in which the slides injection piston topped with a conical tip whose diameter decreases as you get closer to the injection end (the nozzle). The surgeon presses on the piston, the end of which pushes the implant; the latter is increasingly forced into the injector nozzle and eventually comes out of the injector completely folded. This makes it possible to inject an implant with a diameter of more than 6mm through an incision smaller than 3 mm. Very high stresses are then exerted on the implant during the transfer. To limit the injection force and allow To ensure the implant is removed from the tip without damage, it is necessary to optimize the the geometry of the tip and the nature of the support on the one hand, and, on the other hand, the use of a "Lubricant".

[0004] — In the remainder of the description, the terms “device” will be used interchangeably intraocular implant injection system", injection system or oph- injector Talmic.

[0005] — Patent applications EP1173115, EP2344073 or WO / 2007 054644 and WO / 2007 021412, for example, describes injection systems with designs Different geometric shapes. Many commercially available injectors relate the different forms and / or mechanical inventions described in the patents. One example is monobloc injectors (tips and injection body are linked). of the Skyjet® type marketed by Carl Zeiss Meditec or injectors Accujet®, Navijet® or Viscojet® from Medicel AG where the tip is removable and consists of an injection chamber in which the implant is placed, which is immediately folded and passes through a cannula to be injected, or Monarch® type injectors from Alcon laboratories where the tip is removable and the implant is slid into the tip without prior folding. The mechanical properties of the material used to manufacture the tip also influence injectability. The thermoplastic material must allow for a certain degree of deformability to accommodate the stresses placed on the implant while maintaining good rigidity. Furthermore, the thermoplastic materials used must be able to be injected at high rates. These materials are preferably chosen from the polypropylene, polyamide, polyurethane, or polyester families, and more specifically from the polypropylene and polyamide families. However, the choice of material for the tip and / or cartridge, along with optimizing its geometry, is not sufficient for successfully injecting implants through micro-incisions. It is essential to use a lubricant that allows the implant to slide smoothly within the tip and / or cartridge. Alternatively, the tip and cartridge can be integrated into a single unit. This alternative is referred to as "tip and / or cartridge" or "tip / cartridge." Two different approaches to achieving sliding are described in the literature. The first involves the use of a blooming agent incorporated into the thermoplastic material by compounding. This is a low molecular weight organic surfactant molecule, such as glycerol monostearate (GMS), which is compounded with polypropylene or polyamide. It is distributed uniformly throughout the thermoplastic substrate immediately after injection and eventually migrates to the substrate surface after several days or even weeks. This migration phenomenon is linked to the small size of the surfactant molecule, which is mobile compared to macromolecular chains. For example, US patent 6733507 describes polypropylene cartridges containing a lubricating agent that migrates to the surface by blooming. This approach has two major drawbacks. The first issue is the presence of white residue on the injected implants. This is due to the migrating agent, which is not bound to the tip surface and is carried away during the injection. Indeed, the migrating agents used are not water-soluble and their removal is only possible after numerous rinses once the implant has been injected. The second drawback is related to the migration of the migrating agent across the surface of the substrate. This migration can last several days, or even several Depending on the implementation conditions (part injection), storage temperature, post-treatment, sterilization conditions, etc., it can take several weeks for a sufficient amount of lubricant to reach the surface of the injection cartridge. The quality of lubrication therefore depends on the waiting time between the injector's manufacture and its use by the practitioner. If this period is too short, lubrication is not adequate, and if it is too long, the implant is covered with white spots (presence of the migrating agent) during injection. To overcome this drawback, application WO2005 / 018505 proposes heat-treating the parts to accelerate the migration process and achieve a near-stable state (sufficient lubricant on the substrate surface), enabling reproducible injections.Another method described in US patent 7348038 suggests plasma treatment to ensure physical bonding of the migration agent to the cartridge. The non-reproducibility of lubrication and the presence of whitish spots on the implants during injection represent the main drawbacks of using migration agents. The second approach to sliding implants into the injector tips / cartridges is the application of a hydrophilic coating inside the tip. The lubrication principle involves swelling the hydrophilic coating by adding a viscous product (hyaluronate solution or...) of hydroxypropylmethyl cellulose) and thus slide on a film of water formed at the interface. Patent applications or patents JP5690838, JP3254752, US5716364, EP1949871, WO96 / 22062, WO2007 / 030009, WO2010 / 118080, US7687097, US7348038, WO2010 / 059655, for example, describe the possibility of making a coating that reduces or eliminates friction between the implant and the cartridge. The hydrophilic coating is bonded either by covalent chemical bonds or by physical bonds to the surface of the tip and / or cartridge. For coatings bonded to the substrate by physical interactions, surface activation by plasma or corona, or other photochemical methods, is systematically recommended, as shown, for example, in patent applications or patents JP5690838, JP3254752, EP1949871, US 5716364, WO2010 / 059655, WO2010 / 118080, and US7348038. Once the surface is activated, the polymer in solution is deposited, and the solvent is then evaporated. Hydrophilic polymers are selected from polyacrylic acid, polymethacrylic acid, polyvinyl acetate, polyacrylamide, polyvinylpyrolidone, and their copolymers, and sometimes a mixture of several of these polymers. However, sometimes the polymers that make up the coating detach from the The coatings may be absorbed by the viscous product and carried into the eye by the implant. If the practitioner does not adequately rinse the eye after implant placement, coating residues can eventually cause inflammation. Coatings covalently bonded to the cartridge and / or tip are also described, notably in patent applications or patents US7687097 and W0O96 / 22062. The recommended approach involves immersing the cartridge, pre-treated or not with plasma, in a precursor with reactive functionalities, such as acrylate groups, and then, through radical irradiation (thermal or UV), initiating polymerization of the precursor. Some of the precursor chains react with the radicals formed on the cartridge surface. Other patent applications or patents, such as US6238799, US6866936, and WO96 / 23602, describe the covalent grafting of hydrophilic polymers, or even hydrogels, onto medical device substrates. The principle is based on the creation of interpenetrating networks made up of a polyurethane bonded to another hydrophilic polymer. However, covalently grafting a coating onto the surface of the tip and / or cartridge of the ophthalmic injector is a lengthy and expensive operation which limits the usefulness of the approach. The aim is therefore to develop a slippery coating that does not require chemical grafting to the surface of the tip and / or the injector cartridge and that does not detach during the injection of the implant. Summary of the invention According to a first aspect, the invention relates to a polymer suitable for forming a slippery coating, of formula (I): [Chem.1] H Hi tepis es B | io, 2 Q «5 in which: - A represents a group —(CH--CH,-O)- - R is chosen from the following groups: [Chem.2] CH4 0% € C te 4 cHs to YS “ Cu Le He Re, Adi C NA - B represents an ether or ester group as defined below: [Chem.3] sv 3 reve a brie 254th: t D CH —0—C—É#H—CH—— ra Tomerfonjr mé re s oO GO - is an integer between 10 and 500, preferably between 20 and 300; - is an integer between | and 50, preferably between | and 20; - is an integer between 4 and 18, preferably between 4 and 10; and - x is an integer chosen so that the number-average molar mass of the polymer is between 20,000 g / mol and 1,000,000 g / mol. The invention also relates to the use of said polymer for coating the internal surface of one or more parts of an intraocular implant injection device, thereby imparting a slippery characteristic, as well as the method for coating said surface, ensuring good adhesion of the polymer. The invention further relates to a part of an intraocular implant injection device, the internal surface of which is coated with a polymer as defined above, and to an intraocular implant injection device comprising at least one part whose internal surface is coated with said polymer. Detailed description The present invention aims to provide slippery coatings for intraocular implant injection devices, which are sufficiently hydrophilic to be swollen by viscous products and ensure their role as a lubricant while being sufficiently hydrophobic to avoid any solubilization and any involuntary dispersion of said coating in the patient's eye, thus avoiding post-operative problems. The invention consists of developing a coating for an ophthalmic injector based on a polymer whose molar masses and hydrophilic-hydrophobic balance are perfectly adjusted to form a film on the surface of an ophthalmic injector tip; this film has the specific characteristics of being slippery, on the one hand, and perfectly water-resistant, on the other. This water resistance prevents any transfer of the polymer into the eye. The "slippery" nature of the coating according to the invention can be measured, for example, using a one-piece ophthalmic injector entirely manufactured by injection molding from said composition, or a two-piece injector in which only the loading cartridge and the nozzle are manufactured from said composition. The thrust force on the injector piston required to eject the implant loaded in the injector cartridge, through a nozzle with an outlet diameter of less than 3 mm, for example 2 mm, is measured. This measurement can be performed by compression using an Instron 3367 type dynamometer equipped with a force sensor with a sensitivity of 0.5 kN at a speed of 4 mm / s and at room temperature. The slippery property is considered significant for force values ​​between 5 and 10 N.It is moderate for force values ​​greater than 10 N and less than 15 N, and low for force values ​​greater than 15 N. Thus, the deposition of a coating according to the invention is considered to give an ophthalmic injector a "slippery" character when a practitioner injects without damage an implant of a diopter less than or equal to 30D into the eye of a patient, applying a force less than or equal to 20N. The invention also relates to the method of applying the coating. The method according to the invention ensures good adhesion of said polymer to the surface of the tip and / or the cartridge of the injector to prevent said coating from being detached and carried away by the implant during its injection into the patient's eye. Advantageously, the slippery coating according to the invention has the following properties: a hydrophilic-hydrophobic balance and adjusted molar masses, film-forming properties, good affinity with polypropylene or polyamide substrates. According to a first aspect of the invention, the polymer constituting the coating according to The invention can be selected from the polyurethane family. The hydrophilic-hydrophobic balance of this type of polymer can be adjusted by choosing the nature and ratio of the polyols and diisocyanates selected. Polyurethanes also possess good film-forming properties; indeed, they are used as varnishes in numerous applications. Finally, their polar nature and their ability to form hydrogen bonds allow them to exhibit a high affinity for many substrates. The invention therefore relates, according to a first aspect, to a polymer suitable for forming a slippery coating, of formula (I): [Chem.1] ï miss fans 2 ô < in which: - A represents a group —(CH--CH,-O)- - R is chosen from the following groups: [Chem.2] { of e CL YS Nb, PO U - B represents an ether or ester group as defined below: [Chem.3] 5 — mms 555 2 ft ——e0Fen— CHA CH; Q = > To een) ——0——e—É8—CH | 3 | 9 Q - is an integer between 10 and 500, preferably between 20 and 300; - is an integer between 1 and 50, preferably between 1 and 20; - is an integer between 4 and 18, preferably between 4 and 10; and - x is an integer chosen so that the number-average molar mass of the polymer is between 20,000 g / mol and 1,000,000 g / mol. According to the invention, the polymer of formula (I) can be obtained with the appropriate hydrophilic-hydrophobic balance by reacting a hydrophilic diol of the dihydroxytelechelic ethylene oxide type with a hydrophobic diol of the HO-B-OH type, B being as defined above, in the presence of a diisocyanate. Said diisocyanate can be selected, for example, from the following compounds: [Chem.4] L oc, NCO Y 7 LA Cha ON. A, f ; NCo ocN, M THERE, VEN hace oc, —%, ON 2008 H ! 3 A As Cha, i L SL nc0 An important parameter for achieving an adequate hydrophilic-hydrophobic balance is the mass ratio between dihydroxytelechelic ethylene oxide and the hydrophobic diol. Preferably, this ratio is between 99:1 and 70:30, and more particularly between 97:3 and 80:20. An advantageous aspect of the polymer constituting the coating according to the invention is its film-forming ability. Indeed, the coating's slipperiness is also linked to the formation of a smooth and homogeneous film. It has been found that polymers with a number-average molar mass greater than 20,000 g / mol result in more homogeneous films. The choice of the number-average molar mass of the polymers used also determines their resistance to water dissolution. The higher the molar mass, the greater the resistance to water dissolution. Preferably, the polymers used according to the invention have number-average molar masses greater than 20,000 g / mol and less than 1,000,000 g / mol, and in particular between 50,000 g / mol and 500,000 g / mol. According to a further aspect of the invention, the method of depositing the polymer film onto the material constituting the tip and / or cartridge of the ophthalmic injector is important to prevent the coating from detaching and being drawn into the patient's eye. Preferably, to ensure good adhesion of the coating to the tip and / or cartridge of the ophthalmic injector, the latter undergoes a specific treatment. First, all traces of deposits, such as grease or particles, are removed from the surface of the tip and / or cartridge by washing, for example, by washing with alcohol followed by rinsing with pure water. The surface of the material is then subjected to a treatment that induces strong oxidation in order to increase the surface tension of the substrate. Thus, the tip and / or cartridge is / are treated with corona, oxygen plasma, or air.The presence of functionalities created by oxidation on the surface of the tip and / or cartridge allows for the easy formation of hydrogen bonds with the coating. Indeed, the systematic presence of urethane bonds in the coating (aided by ester bonds for coatings that contain them) ensures very good adhesion to the substrate treated by corona, or plasma with argon, oxygen, or air, particularly thanks to the hydrogen bonds. The coating using the polymer according to the invention is preferably applied using a solvent. The polymer is dissolved at a concentration of 0.5% to 3% in a polymer solvent, preferably a mixture of water and ethanol. The nozzle and / or cartridge is / are filled with this solution. After a few seconds, for example, about 3 seconds, the excess is drained away; the polymer deposited on the surface of the nozzle and / or cartridge is then dried. The resulting film is smooth and homogeneous. Injection tests performed with these tips / cartridges coated according to the various aspects of the invention enabled easy injection of the implants, including small diameters (<3 mm), without detachment or solubilization of the coating. No trace of the polymer constituting the coating could be found by HPLC analysis, either on the surface of the implants or in the medium in which they were tested. implants were injected. Examples Example | : preparation of a polyurethane whose diol part is composed of polyethylene oxide and poly(e-caprolactone). 400g of a dihydroxytelechelic POE having a number-average molar mass of 6000g / mol (6.67 x 10⁻³ mol) and 100g of a dihydroxytelechelic poly(ε-caprolactone) (8 x 10⁷ mol) with a molar mass of 1250 g / mol are dried under vacuum for 2 hours at 100°C and then solubilized in 1.45 liters of butanone previously dried over CaCl₂. The solution is heated to 85°C at the time of the introduction of 38.43g of 4,4-methylene biscyclohexyl diisocyanate (14.67 x 10⁻³ mol). 0.5g of a bismuth-based catalyst is added 5 minutes after the end of the isocyanate introduction. The reaction is terminated after 19 hours by the addition of 1 ml of ethanol. The solution is cooled to room temperature, then diluted in 1.5 L of acetone and precipitated in 8 L of heptane. The number-average molar mass of the polymer obtained (PS equivalent) is 25,000 g / mol. Example 2: Preparation of a polyurethane whose diol portion is composed of ethylene polyethylene oxide and decanediol 400 g of a dihydroxytelechelic POE with a number-average molar mass of 6,000 g / mol (6.67 x 10⁻³ mol) and 10 g of decanediol (5.74 x 10⁻³ mol) with a molar mass of 174 g / mol are dried under vacuum for 2 hours at 100°C and then dissolved in 1.45 liters of 2-butanone previously dried over CaCl₂. The solution is heated to 85°C at the time of the introduction of 20 g of toluene diisocyanate (11.5 x 10⁻³ mol). 0.5 g of a bismuth-based catalyst is added 5 minutes after the isocyanate has been added. The reaction is terminated after 19 hours by the addition of 1 ml of ethanol. The solution is cooled to room temperature, then diluted in 1.5 L of acetone and precipitated in 8 L of heptane. The number-average molar mass of the polymer obtained (PS equivalent) is 85,000 g / mol. Example 3: Preparation of a polyurethane whose diol portion is composed of polyethylene oxide and propylene oxide 400 g of dihydroxytelechelic POE with a number-average molar mass of 6000 g / mol (6.67 x 10⁷ mol) and 100 g of dihydroxytelechelic propylene polyethylene oxide (10 x 10⁻³ mol) with a molar mass of 1000 g / mol are dried under vacuum for 2 hours at 100°C and then solubilized in 1.45 liters of 2-butanone previously dried over CaCl₂. The solution is heated to 85°C at the time of the introduction of 37.05 g of toluene diisocyanate (16.67.10? mole). 0.5 g of a bismuth-based catalyst is added 5 minutes after the end of the isocyanate introduction. The reaction is terminated after 19 hours by the addition of 1 ml of ethanol. The solution is cooled to room temperature, then diluted in 1.5 L of acetone and precipitated in 8 L of heptane. The number molar mass of the polymer obtained (PS equivalent) is 63,000 g / mol. Example 4: Treatment of nozzles and cartridges before application of the coating according to the invention The nozzles / cartridges are washed twice with ethanol and then rinsed twice with pure water. They are then dried with compressed air. The device used for plasma treatment is a PlasmaNet MWGO. The gas used is air at a pressure of 0.4 mbar. The gas usage time is 20 seconds, and the plasma treatment lasts 195 seconds at a power of 3000 W. The surface tension of the nozzles / cartridges is determined using test inks after plasma treatment to ensure its effectiveness. At the end of the cycle, samples of the nozzles / cartridges are taken; ACOTEST 56 mN / m ink is deposited on the surface of the substrates. The plasma treatment is validated if the ink spreads perfectly. Example 5: application of the invention The polymer from Example 1 is solubilized at 1% in a 70% water / 30% alcohol mixture for 24 hours at room temperature. The solution is then filtered through a 0.2 µm filter. The solution is ready for application. The nozzles / cartridges are filled with the solution prepared above. The excess is removed under vacuum after approximately 3 seconds of contact. The deposit is then dried at 40°C for 24 hours. The resulting film is smooth and homogeneous. Example 6: Injection tests carried out with coatings made from different polymers are reported in Table 1 below. The measurement was carried out by compression using an Instron 3367 type dynamometer equipped with a force sensor with a sensitivity of 0.5 kN at a speed of 4 mm / s and at ambient temperature. [Table 1] [Reference [Lens Diameter |Type of re- Force IOL of tip |outlet clothing (N) - |26 mm - [Example 2 Nature / Diopter DIS15042B | Hydrophilic / 24.5 |DIS15042A - |26 mm Mean Standard deviation [Example 3 15042A | Hydrophilic / 24.5 [Average Standard deviation |DIS15047D3 [Hydrophite / 17 |20mm | |Example 1 Mean Standard deviation [DIS15047D1 |Hydrophilic / 17 |20 mm [Example 3 Standard deviation DIS15055B1 |Hydrophilic / 17 |20mm | |Example 1 es re |Example 3 Mean Standard deviation [DIS15055B2 |Hydrophilic / 28 20 mm [Example 1 Mean Standard deviation The results show that the deposited coating gives the injector a sliding characteristic allowing the injection of an intraocular implant of at least 6 mm in diameter through a tip of 2 mm in diameter. Example 7: 50 hydrophilic implants of diopter 28 were injected using an injector with a 2 mm diameter tip (treated according to the protocol of example 5) in a pure water bath at 32°C. The water bath containing the implants was concentrated using a rotavator and then lyophilized. The residual solution was analyzed by HPLC (water / acetonitrile). No trace of the coating from Example 1 was found in the analyzed product.

Claims

Demands

1. Polymer capable of forming a slippery coating, of formula (1): [Chem.1] r 1 EE + A i ha eaée tek * D © ds in which: - A represents a grouping —(CH,-CH,-0)- ; - R is chosen from the following groups: [Chem.2] eR Company Tee at 7 fa y CU CH, ÿS SS “ps ie, — Ste A kg ŸS C4 re Se, SA, Miss LA rie - B represents an ether or ester group as defined below: [Chem.3] =} [} {dc 2}{; = + ——o0pen)— CHA ee re re fre ve 9th oi ee —— Om Om H s Il Hair Q Oo - is an integer between 10 and 500, preferably between 20 and 300; - mest is an integer between 1 and 50, preferably between 1 and 20: - s is an integer between 4 and 18, preferably between 4 and 10: and - x being an integer chosen such that the average molar mass the polymer number should be between 20,000 g / mol and 1,000,000 g / mol, preferably between 50,000 g / mol and 500,000 g / mol.

2. Polymer of formula (I) according to claim 1, obtained by making react a hydrophilic diol of the dihydroxytele- type ethylene polyethylene oxide chelic acid with a hydrophobic diol selected from poly(e-caprolactone) or decanediol in the presence of a diisocyanate.

3. Polymer of formula (I) according to claim 1 or 2, obtained by reacting a hydrophilic diol of the ethylene polyethylene dihy- type droxytelechel with a hydrophobic diol in the presence of a dii- socyanate selected from 4,4'-methylene biscyclohexyl diisocyanate and toluene diisocyanate.

4. A method for obtaining a polymer of formula (I) according to claim 1, comprising the reaction of a hydrophilic diol of the polyoxide type dihydroxyethylenetelechelic with a hydrophobic diol HO-B-OH in which B is such as defined in claim 1 in the presence of a diisocyanate, the mass ratio between ethylene polyethylene dihy- droxytelechel and the hydrophobic diol being between 99 / 1 and 70 / 30.

5. Use of a polymer of formula (I) according to any one of the re- claims 1 to 3 or obtained according to the process of claim 4 for the coating of the internal surface of one or more parts of a intraocular implant injection device.

6. Use according to claim 5, wherein said part is the tip and / or cartridge of an ophthalmic injector.

7. Method for coating the internal surface of one or more parts of an intraocular implant injection device, including the Next steps: - submit the internal surface of the part(s) of the device injection of intraocular implants to be coated, in particular the tip and / or the cartridge, to a strongly oxidizing treatment, and - deposit a polymer solution, as defined in any claims 1 to 3.

8. A method according to claim 7, wherein the treatment strongly oxidant of the internal surface is a treatment for corona, plasma at oxygen or air.

9. A method according to any one of claims 7 or 8, wherein the polymer is solubilized in a solvent of said polymer, at a concentration of from 0.5% to 3%.

10. A method according to any one of claims 7 to 9, wherein the the part of the injector to be coated is filled using the solution of polymer, then dried, after removal of excess.

11. | A method according to any one of claims 7 to 10, comprising in addition a preliminary step of specific treatment of the(s) part(s) of the intraocular implant injection device to be coated in order to to eliminate all traces of deposits on its surface.

12. Part of an intraocular implant injection device, the surface The internal part is coated with a polymer according to any one of the following claims: instructions 1 to 3.

13. Intraocular implant injection device comprising at least one part whose internal surface is coated with a polymer according to one any of the claims | to 3.