Aqueous viscoelastic solution and use thereof in an injection device

Abstract

The invention relates to an aqueous viscoelastic solution comprising: at least one polymer selected from among hyaluronic acid and the salts thereof, and cellulosic derivatives and the salts thereof, in particular hydroxypropyl methylcellulose and the salts thereof; and at least one water-soluble polymer of the polyether-polyurethane or polyether-polyester-urethane type, and to the use thereof in a device intended for the injection of an intraocular implant.

Claims

1. An aqueous viscoelastic solution comprising: at least one polymer selected from hyaluronic acid and salts thereof, and cellulosic derivatives and salts thereof, and at least one water-soluble polymer of the polyether polyurethane or polyether polyester urethane type, said viscoelastic solution having a viscosity comprised between 10 and 7000 Pa.Math.s, and wherein said water-soluble polymer of the polyether polyurethane or polyether polyester urethane type does not have a terminal or pendant fatty acid chain comprising at least 10 carbon atoms.

2. The viscoelastic solution according to claim 1, in which the hyaluronic acid has a weight average molecular weight comprised between 1.5 MDa and 5 MDa.

3. The viscoelastic solution according to claim 1, wherein the hyaluronic acid has a weight average molecular weight comprised between 0.5 MDa and 1.5 MDa.

4. The viscoelastic solution according to claim 1, in which the hyaluronic acid is in the form of sodium or potassium hyaluronate.

5. The viscoelastic solution according to claim 1, in which said cellulosic derivative is hydroxypropyl methylcellulose or one of the salts thereof.

6. The viscoelastic solution according to claim 1, in which the content of polymer selected from hyaluronic acid and salts thereof, and cellulosic derivatives and salts thereof, is comprised between 0.5 and 3%, expressed in weight/volume.

7. The viscoelastic solution according to claim 1, in which the water-soluble polymer of the polyether polyurethane type is an ethylene oxide and propylene oxide block copolymer.

8. The viscoelastic solution according to claim 7, in which the water-soluble polymer of the polyether polyurethane type is a branched ethylene oxide and propylene oxide block copolymer comprising urethane, allophanate and urea bridges.

9. The viscoelastic solution according to claim 7, in which said water-soluble polymer of the polyether polyurethane type has a weight average molecular weight greater than or equal to 20 KDa.

10. The viscoelastic solution according to claim 1, in which the water-soluble polymer of the polyether polyester urethane type is a branched polyether and polyester copolymer comprising urethane, allophanate and urea bridges.

11. The viscoelastic solution according to claim 10, in which said water-soluble polymer of the polyether polyester urethane type has a weight average molecular weight greater than or equal to 20 KDa.

12. The viscoelastic solution according to claim 1, in which the content of water-soluble polymer of the polyether polyurethane or polyether polyester urethane type in the aqueous viscoelastic solution is comprised between 0.10 and 0.5%, expressed as weight/volume.

13. A method for injection of an intraocular implant into an eye comprising: injecting an intraocular implant into an eye with a device intended for injection, wherein said device contains an aqueous viscoelastic solution comprising: at least one polymer selected from hyaluronic acid and salts thereof, and cellulosic derivatives and salts thereof, and at least one water-soluble polymer of the polyether polyurethane or polyether polyester urethane type, said viscoelastic solution having a viscosity comprised between 10 and 7000 Pa.Math.s, and wherein said water-soluble polymer of the polyether polyurethane or polyether polyester urethane type does not have a terminal or pendant fatty acid chain comprising at least 10 carbon atoms.

14. The method according to claim 13, wherein said device comprises an injection body, a tip, a loading cartridge and an injection piston.

15. The method according to claim 13, wherein said aqueous viscoelastic solution makes it possible to reduce the force to be exerted on the piston of said device.

16. The method according to claim 14, wherein said viscoelastic solution is introduced into said loading cartridge before, or simultaneously with, the loading of the intraocular implant.

17. The method according to claim 13, wherein said viscoelastic solution makes it possible to apply an injection force less than 30 N, on the piston of an injection device equipped with a tip having an aperture of diameter equal to or less than 2.6 mm.

18. A device for the injection of an intraocular implant, comprising an injection body, a loading cartridge and an injection piston, wherein the loading cartridge contains a viscoelastic solution of claim 1.

19. The viscoelastic solution according to claim 1, further comprising a hydrophilic or hydrophobic intraocular implant.

Description

Example 1: Preparation of a Water-Soluble Polymer of the Polyether Polyurethane Type (EG230)

(1) The EG230 polymer is a polyurethane composed of a triblock ethylene oxide-propylene oxide-ethylene oxide copolymer linked together by urethane, allophanate and urea bonds. The EG230 polymer is obtained by reaction between the polymers having hydroxyl groups and an isocyanate reagent.

(2) ADEKA NOL F-108 is dried in a reactor under vacuum and under continuous stirring at 120° C. so that all of the water is removed. PEG 600 is placed in a heatproof, vacuum-proof vessel and left to melt under vacuum at 80° C. until melting is complete.

(3) After cooling the reactor containing the F-108 to a temperature of approximately 70° C., the 2-butanone previously dried over CaCl.sub.2 and filtered is added under nitrogen, then water, dicyclohexylmethane 4,4′-diisodicyanate and tin dibutyl dilaurate (catalyst). The reagents are mixed while maintaining the heating.

(4) When the conversion of the isocyanate functions reaches 58%, the dry, liquid PEG 600 (80° C.) is added in one go under a nitrogen stream. The heating is stopped when at least 99% of the isocyanates are consumed.

(5) After stopping the nitrogen stream, ethanol is added to the reaction medium under stirring during 30 min. The EG230 polymer is precipitated from 1.5 times the volume of reaction medium and dried at 40° C. under vacuum.

(6) The composition thereof is given in Table 1 below:

(7) TABLE-US-00001 TABLE 1 Molecular Molar Weight Ratio (g/mol) Weight (g) ADEKA NOL F-108 1 — 300 (marketed by ADEKA) Dicyclohexylmethane 2.06 262 15 4,4′-diisocyanate polyethylene glycol (PEG 1.73 600 35 600) monomethyl ether Dry 2-butanone — 900 mL Demineralized water 0.2 g/100 g 0.6 F-108 Tin dibutyl dilaurate 500 ppm/ 0.15 F-108 Ethanol 99% 100 mL/100 kg 100 mL undenatured F-108

Example 2: Preparation of a Water-Soluble Polymer of the Polyether Polyurethane Type (EG68(0))

(8) ExpertGel EG68(0) is a polyurethane composed of a triblock ethylene oxide-propylene oxide-ethylene oxide copolymer linked together by urethane, allophanate and urea bonds. ExpertGel EG68(0) is obtained by reaction between the polymers representing hydroxyl groups and an isocyanate reagent.

(9) Briefly, Lutrol F68 (Kolliphor P188) is dried in a reactor under vacuum and under continuous stirring at 120° C. so that all of the water is removed. The PEG 600 is placed in a heatproof and vacuum-proof vessel and left to melt under vacuum at 80° C. until melting is complete.

(10) After cooling of the reactor containing the F68 to a temperature of approximately 70° C., the 2-butanone previously dried over CaCl.sub.2) and filtered is added under nitrogen, then water, dicyclohexylmethane 4,4′-diisodicyanate and tin dibutyl dilaurate (catalyst). The reagents are mixed while maintaining the heating.

(11) When the conversion of the isocyanate functions reaches 58%, the dry, liquid PEG 600 (80° C.) is added in one go under a nitrogen stream. The heating is stopped when at least 99% of the isocyanates are consumed.

(12) After stopping the nitrogen stream, ethanol is added to the reaction medium under stirring during 30 min. The EG68(0) polymer is precipitated from 1.5 times the volume of reaction medium and dried at 40° C. under vacuum.

(13) The composition thereof is given in Table 2 below:

(14) TABLE-US-00002 TABLE 2 Molecular Molar Weight Ratio (g/mol) Weight (g) Lutrol F68 (Kolliphor 1 — 300 ± 3 P188 marketed by BASF) Dicyclohexylmethane- 2.06 262 18.4 4,4′ diisocyanate Polyethylene glycol 1.82 600 37.1 (PEG 600) monomethyl ether Tin dibutyl dilaurate 500 ppm/ 0.15 F68 Dry 2-butanone — 0.9 L Demineralized water 0.2 g/100 g 0.6 F68 Ethanol 99% 5 mL/kg F68 0.15 undenatured

Example 3: Preparation of a Water-Soluble Polymer of the Polyether Polyurethane Type (EG88(0))

(15) The EG88(0) polymer is a polyurethane composed of a triblock ethylene oxide-propylene oxide-ethylene oxide copolymer linked together by urethane, allophanate and urea bonds. The EG88(0) polymer is obtained by reaction between the polymers representing hydroxyl groups and an isocyanate reagent. The synthesis protocol is similar to that of the EG68(0) polymer in Example 2, but replacing Lutrol F68 with Lutrol F88.

(16) The composition thereof is given in Table 3 below:

(17) TABLE-US-00003 TABLE 3 Molecular Molar Weight Ratio (g/mol) Weight (g) Lutrol F88 (marketed by 1 — 300 ± 3 BASF) Dicyclohexylmethane- 2.06 262 14.2 4,4′ diisocyanate Polyethylene glycol 1.82 600 28.7 (PEG 600) monomethyl ether Tin dibutyl dilaurate 500 ppm/ 0.15 F88 Dry 2-butanone — 0.9 L Demineralized water 0.2 g/100 g 0.6 F88 Ethanol 99% 5 mL/kg F88 0.15 undenatured

Example 4: Preparation of a Water-Soluble Polymer of the Polyether Polyester Urethane Type (ES)

(18) The ES polymer is a branched polyether and polyester copolymer having urethane and allophanate bridges (and very little urea). It is obtained by reaction of a dihydroxytelechelic polycaprolactone and a polyethylene glycol and a diisocyanate.

(19) Briefly, the polycaprolactone (CAPA) and the PEG are dried in a reactor under vacuum and under continuous stirring at 100° C. When the CAPA and the PEG are completely melted, the heating and the vacuum are maintained, so that all of the water contained in the polymers is removed.

(20) After cooling the reactor to a temperature of approximately 80° C., the 2-butanone previously dried over CaCl.sub.2 and filtered is added under nitrogen, then dicyclohexylmethane 4,4′ diisocyanate and bismuth carboxylate (catalyst). The reagents are mixed while maintaining the heating for at least 15 h at 60° C.

(21) After stopping the nitrogen stream, ethanol is added to the reaction medium under stirring during 30 min, then the absence of isocyanate is verified. The reaction medium is diluted with 17 L of 2-butanone, then the final ES polymer is precipitated from heptane and dried at 40° C. under vacuum.

(22) The composition thereof is given in Table 4 below:

(23) TABLE-US-00004 TABLE 4 Weight (g) Polycaprolactone CAPA 2125 305.5 (marketed by Perstorp) Polyethylene glycol (PEG 6000) 6700 monomethyl ether Dicyclohexylmethane-4,4′ 329.2 diisocyanate Bismuth carboxylate 3.5 Dry 2-butanone 3.08 L Ethanol 99% pure 10 mL

Example 5: Preparation of an Aqueous Viscoelastic Solution Comprising a Water-Soluble Polymer of the Polyether Polyurethane or Polyether Polyester Urethane Type with 0.25% Weight/Volume

(24) The first part of the preparation is carried out in a clean room. A 2.5% weight/volume solution of water-soluble polymer of polyether urethane type such as those indicated in Examples 1 to 3 or polyether polyester urethane such as the one in Example 4 is produced by dissolution under mechanical stirring by introducing the polymer (2.5 g) in powder form into isotonic water buffered at pH 7 (97.5 mL). After complete dissolution, the solution is sterilized by filtration at 0.2 microns on a nylon filter. Sodium hyaluronate is added (16 g) in powder form to the polymer solution and 884 mL of buffered isotonic water is added in order to adjust the concentrations. The mixture is shaken on an orbital mixer at a speed of 300 rpm at ambient temperature until complete dissolution of the sodium hyaluronate.

(25) After approximately 30 h of solubilization, the aqueous viscoelastic solution comprising 16 mg/mL of sodium hyaluronate (1.6%) and 2.5 mg/mL water-soluble polymer of polyether polyurethane or polyether polyester urethane (0.25%) type is placed in the syringe.

Example 6: Packaging of the Aqueous Viscoelastic Solutions Comprising Sodium Hyaluronate and a Water-Soluble Polymer of the Polyether Polyurethane or Polyether Polyester Urethane Type

(26) The pre-sterilized syringes are filled with 1.1 mL of solution. They are then sterilized in an autoclave.

(27) The secondary wrapping in a polyester blister pack is then carried out before proceeding to a fresh sterilization by ethylene oxide (ETO).

Example 7: Aqueous Viscoelastic Solutions Comprising a Water-Soluble Polymer of the Polyether Polyurethane Type and Sodium Hyaluronate (NaHA)

(28) Different aqueous viscoelastic solutions according to the invention and the characteristics thereof are given in Table 5 below.

(29) TABLE-US-00005 TABLE 5 Polymer in the HA Polymer HA Molar Viscosity* solution concentration concentration Weight (Pa .Math. s) EG230 16 mg/mL 2.5 mg/mL 1.9 MDa 130 0.25% EG230 16 mg/mL 1.0 mg/mL 1.9 MDa 110 0.1% EG88(0) 16 mg/mL 2.5 mg/mL 1.9 MDa 135 0.25% EG88(0) 16 mg/mL 1.0 mg/mL 1.9 MDa 110 0.1% EG68(0) 16 mg/mL 2.5 mg/mL 1.9 MDa 90 0.25% EG68(0) 16 mg/mL 1.0 mg/mL 1.9 MDa 100 0.1% *at a zero shear rate determined by a TA rheometer of the AR1500EX type, aluminium cone-and-plate geometry, 40 mm, 63 μm, 2°, T = 25° C.

Example 8: Tests of the Injection of Intraocular Lenses (Iol) in the Presence of Aqueous Viscoelastic Solutions Comprising a Water-Soluble Polymer of the Polyether Polyurethane or Polyether Polyester Urethane Type

(30) The tests were carried out with certain viscoelastic solutions of Example 7, by using cartridges without any treatment promoting the ejection of the lens (no coating or GMS).

(31) The following procedure was followed:

(32) An ophthalmic implant was introduced into the loading cartridge of an injection system comprising an injection body, a loading cartridge (that has not undergone any treatment of the coating or GMS type) and an injection piston.

(33) A viscoelastic solution according to the invention is added thereto, namely a solution of NaHA or HPMC combined with a polymer allowing slipperiness in said loading cartridge. The injection system is placed in a dynamometer of the Instron 3367 type equipped with a force sensor of 0.5 kN sensitivity, at a compression velocity of 8.5 mm/s. The compression force necessary for the injection of the implant is measured, in comparison with a viscoelastic solution on the market containing only NaHA (Visthesia® solution marketed by Zeiss) or a viscoelastic solution containing HMPC only.

(34) The results are given in Tables 6 and 7 below.

(35) 1) Injection of a hydrophilic intraocuiar lens (IOL) through a non-coated Viscoject tip of inside diameter 2.0 mm (commercial IOL AcriLISA® from Zeiss)

(36) TABLE-US-00006 TABLE 6 Nature of the viscoelastic Injection force (N) solution 17 dioptres 28 dioptres NaHA 1.6%-EG88(0) 0.25% 11 +/− 1 12 +/− 1 NaHA 1.6%-EG88(0) 0.10% 12 +/− 2 14 +/− 1 NaHA 1.6%-EG230 0.25% 13 +/− 2 12 +/− 0 NaHA 1.6%-EG230 0.10% 13 +/− 2 12 +/− 0 NaHA 1.6%-EG68(0) 0.25% —  12 +/− 0* NaHA 1.6%-EG68(0) 0.10% —  12 +/− 1* NaHA 1.6%-ES 0.25% 10 +/− 0 13 +/− 3 NaHA 1.6%-ES 0.10% 14 +/− 2 17 +/− 1 Visthesia ® solution (Zeiss) Not ejected Not ejected HPMC* 1.5%-EG68(0) 16 +/− 1 18 +/− 2 0.25% HPMC* 1.5% Not ejected Not ejected *HPMC of molar weight 800 KDa

(37) 2) Injection of a hydrophobic intraocular lens (IOL) through a non-coated Viscoject tip of inside diameter 2.6 mm (commercial IOL Hydromax® from Zeiss)

(38) TABLE-US-00007 TABLE 7 Nature of the viscoelastic Injection force (N) solution 11 dioptres 28 dioptres NaHA 1.6%-EG88(0) 0.25% 18 +/− 4 27 +/− 0 NaHA 1.6%-EG88(0) 0.10% 16 +/− 1 28 +/− 1 NaHA 1.6%-EG230 0.25% 15 +/− 3 21 +/− 3 NaHA 1.6%-EG230 0.10% 14 +/− 0 24 +/− 0 NaHA 1.6%-EG68(0) 0.25% — — NaHA 1.6%-EG68(0) 0.10% — 29 +/− 0 NaHA 1.6%-Es 0.25% 20 +/− 4 27 +/− 4 NaHA 1.6%--Es 0.10% 24 +/− 1 29 +/− 2 Visthesia ® solution (Zeiss) Not ejected Not ejected

(39) The results show that the presence of slippery viscoelastic solution (solution containing sodium hyaluronate or hydroxypropyl methylcellulose combined with a polymer of the polyether urethane or also polyether polyester urethane type) during injection allows intraocular lenses, having a hydrophobic, hydrophilic nature or also hydrophilic with a hydrophobic surface, to be injected through a small-diameter tip, with injection forces less than 30 N. These tests were carried out with cartridges without any treatment promoting the ejection of the intraocular lens. On this same device, the ejection of an intraocular lens, even having low dioptre units, by means of a solution containing only sodium hyaluronate or hydroxypropyl methylcellulose (without slippery polymer) is not possible.

(40) The values for the injection force measured in the presence of the viscoelastic solutions used according to the invention are comparable to those measured for injector tips coated with a slippery polymer and using a standard viscoelastic solution.

(41) By way of comparison, the force necessary to inject a hydrophilic implant of the AcriLISA® type of 28 dioptres by means of a Viscoject cartridge of 2 mm diameter coated with a slippery polymer is 13 N+/−1.