Ophthalmic compositions comprising polyether substituted polymers

Abstract

The present invention relates to ophthalmic solutions and devices comprising at least one water soluble polymer having a molecular weight of at least about 500,000 Daltons and comprising linear or branched polyether pendant groups having a molecular weight of at least about 300.

Claims

1. An ophthalmic device comprising at least one water soluble polymer having a molecular weight of at least about 500,000 Daltons and comprising linear or branched polyether pendant groups having a molecular weight of at least about 300, wherein the polyether pendant groups provide a hydrophilic, brush or comb-like structure to the water soluble polymer.

2. The device of claim 1 where said polyether pendant groups are derived from monomers of the Formula I
A-[(CZ.sub.pH.sub.q).sub.yO].sub.nCH.sub.mX.sub.3-m wherein n is 7 or greater; Z is a C.sub.1-C.sub.6 substituted or unsubstituted alkyl group, q is 0, 1 or 2 and p is 2-q, y is 2 to 4, m is 1 or 2; A is any free radical polymerizable group and X is a substituent independently selected from the group consisting of H, hydroxyl, unsubstituted straight or branched alkyl groups, substituted straight or branched alkyl groups, substituted and un substituted amines, substituted and un substituted amides, mercaptans, ethers and esters.

3. The device of claim 2 wherein X is selected from substituted or unsubstituted straight or branched C1-16 alkyl groups.

4. The device of claim 3 wherein X is selected from is selected from substituted or unsubstituted straight or branched C1-12 alkyl groups.

5. The device of claim 3 wherein said alkyl group is substituted with a group selected from the group consisting of carboxylic acids, esters, acyl halides, amines, amides, ketones, aldehydes, halides, sulfides, mercaptans, quartenary ammonium salts and combinations thereof.

6. The device of claim 3 wherein n is an integer of between 7 to 50.

7. The device of claim 3 wherein n is an integer of between 7 to 40.

8. The device of claim 1 wherein said polymer comprises at least about 20% of backbone units have a pendant group bound thereto.

9. The device of claim 1 wherein said polymer comprises at least about 30% of backbone units have a pendant group bound thereto.

10. The device of claim 2 wherein at least about 20% of said pendant groups are polyether pendant groups of Formula I.

11. The device of claim 2 wherein at least about 60% of said pendant groups are polyether pendant groups of Formula I.

12. The device of claim 2 wherein at least about 75% of said pendant groups are polyether pendant groups of Formula I.

13. The device of claim 1 wherein said pendant groups further comprise at least one second pendant group selected from the group consisting of silicones, sugars, carbohydrates, polyethers, amides, lactams, sulfonic acids, sulfonates, amines, hydroxyls, ethers, esters, aldehydes, ketones, amino acids, methacrylated long chain hydrocarbons, polymerizable ionic compounds, reactive latent compounds which may be converted to ionic groups after the water soluble polymer is polymerized and combinations thereof.

14. The device of claim 1 wherein said pendant groups further comprise at least one second pendant group selected from the group consisting of amides, lactams, glycosylated materials, polymerizable ionic compounds and combinations thereof.

15. The device of claim 1 wherein said pendant groups further comprise at least one second pendant group selected from the group consisting lauryl methacrylate, butyl methacrylate, isopropyl methacrylate, methyl methacrylate, phenyl methacrylate, hydroxyethyl methacrylate, methacrylic acid, glycerol monomethacrylate, hydroxyethyl methacrylamide, 2-(-4-morpholinyl)ethyl methacrylate, morpholinyl methacrylamide, 2-(N,N-dimethylamino)ethyl methacrylate, dimethylacrylamide, N-vinyl pyrrolidone, N-vinyl-N-methylacetamide, styrene sulfonate, sodium 2- acrylamido-2-methyl-l-propanesulfonate, sulfopropylacrylamide and combinations thereof.

16. An ophthalmic solution comprising at least one water soluble polymer having a molecular weight of at least about 500,000 Daltons and comprising linear or branched polyether pendant groups having a molecular weight of at least about 300, wherein the polyether pendant groups provide a hydrophilic, brush or comb-like structure to the water soluble polymer.

17. The solution of claim 16 wherein said polyether pendant groups are derived from monomers of the Formula I
A-[(CZ.sub.pH.sub.q).sub.yO].sub.nCH.sub.mX.sub.3-m wherein n is greater than 7; Z is a C.sub.1-C.sub.6 substituted or unsubstituted alkyl group, q is 0, 1 or 2 and p is 2-q, y is 2 to 4, m is 1 or 2; A is any free radical polymerizable group and X is a substituent independently selected from the group consisting of H, hydroxyl, unsubstituted straight or branched alkyl groups, substituted straight or branched alkyl groups, substituted and unsubstituted amines, substituted and unsubstituted amides, mercaptans, ethers and esters.

18. The solution of claim 17 wherein X is selected from substituted or unsubstituted straight or branched C1-16 alkyl groups.

19. The solution of claim 17 wherein X is selected from is selected from substituted or unsubstituted straight or branched C1-12 alkyl groups.

20. The solution of claim 18 wherein said alkyl group is substituted with a group selected from the group consisting of carboxylic acids, esters, acyl halides, amines, amides, ketones, aldehydes, halides, sulfides, mercaptans, quartenary ammonium salts and combinations thereof.

21. The solution of claim 17 wherein n is an integer of between 7 to 50.

22. The solution of claim 16 wherein said polymer comprises at least about 20% of backbone units have a pendant group bound thereto.

23. The solution of claim 16 wherein said pendant groups further comprise at least one second pendant group selected from the group consisting of amides, lactams, glycosylated materials, polymerizable ionic compounds and combinations thereof.

24. The solution of claim 16 wherein said pendant groups further comprise at least one second pendant group selected from the group consisting lauryl methacrylate, butyl methacrylate, isopropyl methacrylate, methyl methacrylate, phenyl methacrylate, hydroxyethyl methacrylate, methacrylic acid, glycerol monomethacrylate, hydroxyethyl methacrylamide, 2-(-4-morpholinyl)ethyl methacrylate, morpholinyl methacrylamide, 2-(N,N-dimethylamino)ethyl methacrylate, dimethylacrylamide, N-vinyl pyrrolidone, N-vinyl-N-methylacetamide, styrene sulfonate, sodium 2- acrylamido-2-methyl-l-propanesulfonate, sulfopropylacrylamide and combinations thereof.

25. The solution of claim 16, wherein said solution is a contact lens packing, storing or cleaning solution.

26. The solution of claim 16, wherein said solution may be directly instilled into the eye.

27. The solution of claim 18 further comprising additional components selected from the group consisting of tonicity adjusting agents, viscosity adjusting agents, antimicrobial agents, polyelectrolytes and mixtures thereof.

28. The solution of claim 17 wherein at least about 20% of said pendant groups are polyether pendant groups of Formula I.

29. The solution of claim 16 wherein said pendant groups further comprise at least one second pendant group selected from the group consisting of silicones, sugars, carbohydrates, polyethers, amides, lactams, sulfonic acids, sulfonates, amines, hydroxyls, ethers, esters, aldehydes, ketones, amino acids, methacrylated long chain hydrocarbons, polymerizable ionic compounds, reactive latent compounds which may be converted to ionic groups after the water soluble polymer is polymerized and combinations thereof.

Description

EXAMPLES

Example 1

(1) The following compounds in the following amounts were mixed to form a homogenous mixture.

(2) TABLE-US-00001 mPEG350 59.66 g Norbloc 7966 340 mg CGI 1850 400 mg Isopropyl acetate 100 mL
The homogeneous mixture was degassed under a vacuum of 80 mm Hg over a period of one hour. The vacuum was interrupted with a positive nitrogen flow on three to four occasions during the degassing process. The material was moved to a glove box, which was under a nitrogen environment. The mixture was transferred to a crystallizing dish and covered with a watch glass. The system was then exposed to visible light (Philips type Tl03 bulbs) for one hour at room temperature to form the desired polymer.

(3) The polymer was precipitated by the addition of 50 mL of hexanes followed by vigorous agitation. The solvent and any soluble material was decanted. Further washes were performed using 300 mL of hexanes followed by thorough mixing and decantation of the liquids. The washing process was continued until the polymer appeared tacky and very thick.

(4) The product was dissolved in 50 mL of ethyl acetate and reprecipitated by the addition of hexanes to the system. The wash process described above was repeated and the product was rid of all solvent in a rotary evaporator at 55 C. Yield of the desired product was 39 g. The material was obtained as a clear, thick paste whose average molecular weight was determined to be 25000 by GPC.

Example 2

(5) The following compounds in the following amounts were mixed to form a homogenous mixture.

(6) TABLE-US-00002 mPEG 475 45 g tert.butyl alcohol 70 mL Norbloc 75 mg CGI1850 300 mg

(7) The homogeneous mixture was degassed for 1 hour under a pressure of 100 mm Hg. The system was purged with nitrogen every 15 minutes during the degassing process. The reaction mixture was transferred to a glove box under a nitrogen atmosphere and into 110 ID175 OD70 mm height silvered crystallizing dish. The dish was placed on a shelf approximately 115 mm from the light source (visible light bulbs, PhilipsTL03). The vessel was covered with a 2 mm thick filter cover (Schott, VG-6, 339732) and the reactants were polymerized for one hour at room temperature.

(8) The polymer was precipitated in a beaker flask (Buchi450 mL) with 100 mL of hexanes and vigorous agitation. The liquids were decanted and the polymer was washed twice with 100 mL of hexanes each time. The residual solid was then dissolved in 50 mL of ethyl acetate, reprecipitated and washed with hexanes as described above. The ethyl acetate/hexanes sequence was repeated once more and some of the crude product (2-4 g) removed, dried under reduced pressure, and in a vacuum oven at 50 C. prior to obtaining molecular weight data by GPC.

(9) An accurately weighed amount (W1) of 2-hydroxyethyl methacrylate (HEMA) was added to the beaker flask (approximately 250 g) and the system is gently mixed on a rotary evaporator until the system is completely homogeneous. The bath was then heated at 40 C. under a vacuum of 10-15 mbar. The evaporation was continued for two hours after the point at which no solvent was being distilled over.

(10) The weight of the beaker flask and solution was accurately measured (W2=weight of flask+polymer+HEMA). After transferring the solution to an appropriate container, the beaker flask was thoroughly cleaned, dried, and accurately weighed (W3=weight of beaker flask).
W2W3=weight of HEMA+polymer=W4
W4W1=total yield of polymer=W5 (typical yield45%)
Concentration of the polymer solution (weight percent) was determined as W5/(W4). Molecular weights (Mn) were determined against polymethyl methacrylate (PMMA) standards to be greater than about 300,000.

Example 3

(11) One weight % of the polymer of Example 1 was added to Packing Solution. 5 ml of the Packing Solution polymer mixture was places in glass vials, and a 1-Day ACUVUE brand contact lens (commercially available from Johnson & Johnson) was placed in the vial. The vial was sealed and autoclaved at 121 C. for 30 minutes. The lenses were allowed to equilibrate after autoclaving for at least about 1 day at ambient temperature.

(12) Five subjects were recruited to wear the test lens in one eye and the control lens in their other eye. The lenses were allowed to settle for 30-minutes prior to any observations.

(13) After 30 minutes, the non-invasive tear break-up time (NIBUT) and lipid layer thickness were observed for both lenses using the Tearscope Plus (Keeler). The test lens was found to have a longer NIBUT than the control lens (10.4 seconds vs. 7.6 seconds). The test lens was also found to have a thicker lipid layer than the control lens in 4 of the 5 of the subjects.

(14) TABLE-US-00003 TABLE 2 Lipid Pattern Ex. #3 1DAY ACUVUE None 0% 0% Open 0% 60% Closed 20% 20% Flow/Wave 60% 0% Amorphous 20% 0% Colours 0% 20%

Example 4

(15) The copolymer (MM-44) formed in Example 2 was used as a monomer component in the formulation listed in Table 3, below.

(16) TABLE-US-00004 TABLE 3 Components Weight % HEMA 95.88 MAA 1.50 Norbloc 1.00 CGI 819 0.50 EGDMA 1.00 BLUE HEMA 0.02 Ex._(MM-44) 0.10

(17) The components were mixed in a glass jar with 40 weight % boric acid glyceryl ester, sealed and rolled on a jar roller until homogeneous.

(18) The lenses were made on a single cavity lens machine utilizing polystyrene+1% zinc front curve and back curve lens molds. Monomer was dosed into the front curve, back curve was deposited, and parts were placed under pre-cure lights for 10 seconds. Molds were cured for 4 minutes at approximately 4 mW/cm.sup.2 and 65 C. Lenses were demolded and placed into leach solution at 705 C. for 18030 minutes, followed by rinse at 455 C. for 15 to 60 minutes and equilibration at 455 C. for a minimum of 3 hours. Lenses were visually inspected, packaged in vials with packing solution and sterilized for 30 minutes at 121 C. Physical properties were measured for the lenses and are shown in Table 4, below.

(19) TABLE-US-00005 TABLE 4 Property Water Content (%) 53.6 0.1 Modulus (psi) 50.9 2.6 Elongation (%) 155.7 49.1 Advancing Contact Angle () 68 6

(20) Thirty myopic, current soft contact lens wearers were recruited to wear test lenses and control lenses (1-DAY ACUVUE). Each lens type was worn daily wear for 1-week and replaced on a daily disposable basis. The study design was a randomized, bilateral cross-over design with investigator masking. Twenty-nine subjects completed the study.

(21) After wearing the lenses for 1-week, the subjects completed preference questionnaires comparing their experiences with both lens types. The lenses from this Example 4 were preferred 2:1 over 1-DAY ACUVUE in the areas of overall comfort, end of day comfort, dryness, wearing time, and moisture. Symptoms reported by the subjects at the 1-week visit were reduced for the test lenses by 50% compared to the control lens.