Nanohybrid polymers for ophthalmic applications

Abstract

The present invention relates to novel materials particularly useful for ophthalmic applications and methods for making and using the same. More particularly, the present invention relates to relatively soft, optically transparent, foldable, high refractive index materials particularly suited for use in the production of intraocular lenses, contact lenses, and other ocular implants and to methods for manufacturing and using the same.

Claims

1. A method of making a copolymer comprising: a) mixing a composition of monomers comprising a fused ring aromatic moiety coupled to a vinylically unsaturated moiety; a hydrophobic monomer; and a hydrophilic monomer for a time period of at least 20 minutes; b) sonicating the composition from step (a) for a time period of at least 10 minutes to produce the copolymer.

2. A method according to claim 1 which includes a further step of mixing the sonicated composition for a time period of at least about 15 minutes.

3. The method of claim 1, wherein said composition further comprises an ultraviolet light absorbing material.

4. The method of claim 1, wherein said composition further comprises an ultraviolet light absorbing material selected from the group consisting of beta-(4-benzotriazoyl-3-hydroxyphenoxy) ethyl acrylate, 4-(2-acryloxyethoxy)-2-hydroxybenzophenone, 4-methacryloxy-2-hydroxybenzo-phenone, 2-(2-methacryloxy-5-methylphenyl)benzo-triazole, 2-(2-hydroxy-5-methacryoxy-ethylphenyl)-2H-benzotriazole, 2-[3-tert-Butyl-2-hydroxy-5-(3-methacyloyloxypropyl)phenyl]-5-chloro-benzotriazole, 2-(3-tert-Butyl-5-(3-dimethylvinylsilylpropoxy)-2-hydroxyphenyl]-5-met-hoxybenzo-triazole, 2-(3-Allyl-2-hydroxy-5-methylphenyl)benzotriazole, 2-[3-tert-Butyl-2-hydroxy-5-[3-methacryloyl-oxypropoxy)phenyl]-5-met-hoxybenzotriazole and 2-[3-tert-Butyl-2-hydroxy-5-(3-methacryloyloxypropoxy)phenyl]-5-chlo- ro-benzotriazole.

5. The method of claim 3, wherein the ultraviolet light absorbing material is vinyl anthracene or derivatives thereof.

6. The method of claim 1, wherein said composition further comprises a monomeric dye.

7. The method of claim 6, wherein the monomeric dye absorbs light in the 400-700 nm region.

8. The method of claim 6, wherein the monomeric dye is disperse red 1 methacrylate.

9. The method of claim 6, wherein the monomeric dye is disperse red 13 methacrylate.

10. The method of claim 6, wherein the monomeric dye is disperse red 1 acrylate.

11. The method of claim 6, wherein the monomeric dye is disperse red 13 acrylate.

12. The method of claim 1, wherein the hydrophilic monomer(s) is selected from the group consisting of 2-hydroxy-ethylacrylate, 2-hydroxyethylmethacrylate, acrylamide, N-ornithine acrylamide, N-(2-hydroxypropyl)acrylamide, polyethyleneglycol acrylates, polyethyleneglycol methacrylates, N-vinyl pyrolidone, N-phenylacrylamide, dimethylaminopropyl methacrylamide, acrylic acid, benzylmethacrylamide, 4-hydroxybutylmethacrylate, glycerol mono methacrylate, glycerol mono acrylate, 2-sulfoethylmethacrylate, phenoxyethyl acrylate, phenoxy ethyl methacrylate, 2-(2-ethoxyethoxyl)ethyl acrylate, 2-(2-ethoxyethoxyl)ethyl methacrylate, furfuryl acrylate, furfuryl methacrylate, and methylthioethylacrylamide.

13. The method of claim 1, wherein the hydrophobic monomer(s) is selected from the group consisting of Lauryl methacrylate, lauryl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, n-decyl acrylate, n-decyl methacrylate, hexyl acrylate, hexyl metcarylate, stearyl acrylate, stearyl methacrylate, isodecyl acrylate, isodecyl methacrylate, isobornyl acrylate, isobornyl methacrylate, vinyl laurate, vinyl stearate, 1-hexadecyl acrylate, 1-hexadecyl methacrylate, n-myristyl acrylate, n-myristyl methacryalte, n-dodecyl methacrylamide, butyl acrylate, n-butyl methacrylate, isooctyl acrylate, isotridecyl acrylate, isooctyl methacrylate, and isotridecyl methacrylate.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Materials of the present invention with high refractive indexes are desirable to allow manufacturers to manufacture thinner IOLs. A thin IOL or thin IOL optic is critical in enabling a surgeon to minimize incision size. Keeping the surgical incision size to a minimum reduces intraoperative trauma and postoperative complications. A thin IOL is also critical for accommodating certain anatomical locations in the eye such as the anterior chamber and the ciliary sulcus. IOLs may be placed in the anterior chamber for increasing visual acuity in both aphakic and phakic eyes and placed in the ciliary sulcus for increasing visual acuity in phakic eyes.

(2) The preferred materials of the present invention have the flexibility required to allow the same to be folded or deformed so that IOLs made therefrom may be introduced into an eye through the smallest possible incision.

(3) The novel materials of the present invention are copolymers, trimers, tetramers, etc., comprising three primary monomeric components: a high refractive index (RI) monomer, a hydrophobic monomer, and a hydrophilic monomer. A cross linker generally is included as is a UV absorber.

(4) A high refractive index (RI) monomer of the present invention comprises a fused ring aromatic moiety coupled to an ethylenically unsaturated or vinylically unsaturated moiety. By the term high refractive index monomer it is intended that a polymer of the high RI monomer (i.e., a homopolymer of the monomer) has a refractive index of at least 1.50, preferably at least 1.53, and most preferably at least 1.56.

(5) A vinylic or ethylene unsaturated moiety is, of course, well known to the art generally to mean a structure of the sort,

(6) ##STR00001##

(7) wherein: R.sub.1-R.sub.4 are separately and independently, H, C, X, or R.sub.c; R.sub.c is any hydrocarbon moiety; and X is any heteratom, providing that at least one of R.sub.1-R.sub.4 must be a fused ring aromatic structure or moiety as is discussed below. The fused ring aromatic structure can be, and often is, R.sub.c.

(8) Fused ring aromatic or polynuclear or polycyclic aromatic moieties are, of course well known. These moieties are characterized by the presence of at least two aromatic rings sharing a pair of carbon atoms. The best known examples of fused ring aromatic moieties are probably naphthalene, carbazole, anthracene, and phenanthrene. Their moieties, i.e., naphthyl, anthracyl, carbazole, and phenanthryl, are examples of preferred moieties of the high RI monomer. Further examples of such fused-ring aromatic molecules and hence their moieties include:

(9) Fused Benzene Ring Compounds

(10) ##STR00002##

(11) The above list is, of course, non-limiting. Further, the unsaturation moiety can be coupled to any one of the outer ring carbons of the above structures as would be readily apparent to one skilled in this art.

(12) In a preferred practice, the high RI monomer comprises multimers including: a carbazole and or naphthyl moiety, the carbazole/naphthyl moiety monomer being present in the composition at a concentration of at least 15% and preferably up to about 25-45%.

(13) The composition further includes a second monomer with a hydrophobic homopolymer, the hydrophobicity being defined as the homopolymer having a surface tension of about 50 dyn/cm or less, the second monomer being present in the copolymer, in an amount of at least about 20 weight percent, preferably about 50-60 weight percent.

(14) The composition further includes at least about 10 weight percent of a hydrophilic monomer, preferably about 20-30 weight percent. The composition then includes a crosslinking monomer, the crosslinking monomer being present at a concentration in the range up to 10 weight percent, preferably of about 1 weight percent to about 8 weight percent.

(15) Suitable hydrophilic monomers (i.e., monomers whose homopolymers are hydrophilic in accordance with this invention) include but are not limited to 2-hydroxy-ethylacrylate, 2-hydroxyethylmethacrylate, acrylamide, N-ornithine acrylamide, N-(2-hydroxypropyl)acrylamide, polyethyleneglycol acrylates, polyethyleneglycol methacrylates, N-vinyl pyrolidone, N-phenylacrylamide, dimethylaminopropyl methacrylamide, acrylic acid, benzylmethacrylamide, 4-hydroxybutylmethacrylate, glycerol mono methacrylate, glycerol mono acrylate, 2-sulfoethylmethacrylate, phenoxyethyl acrylate, phenoxy ethyl methacylate, 2-(2-ethoxyethoxyl)ethyl acrylate, 2-(2-ethoxyethoxyl)ethyl methacrylate, furfuryl acrylate, furfuryl methacrylate, and methylthioethylacrylamide.

(16) Suitable hydrophobic monomers (i.e., monomers whose homopolymers are hydrophobic in accordance with this invention) include, but are not limited to, Lauryl methacrylate, lauryl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, n-decyl acrylate, n-decyl methacrylate, hexyl acrylate, hexyl metcarylate, stearyl acrylate, stearyl methacrylate, isodecyl acrylate, isodecyl methacrylate, isobornyl acrylate, isobornyl methacrylate, vinyl laurate, vinyl stearate, 1-hexadecyl acrylate, 1-hexadecyl methacrylate, n-myristyl acrylate, n-myristyl methacryalte, n-dodecyl methacrylamide, butyl acrylate, n-butyl methacrylate, isooctyl acrylate, isotridecyl acrylate, isooctyl methacrylate, and isotridecyl methacrylate.

(17) Suitable crosslinkers include, for example, but are not limited to, ethylene glycol dimethacrylate (EGDMDA), diethylene glycol dimethacrylate, and triethylene glycol dimethacrylate and poly (ethylene glycol)dimethacrylate wherein ethylene glycol dimethacrylate is preferred. Suitable initiators include, for example, but are not limited to, azobis(isobutyronitrile), 2,2-azobis(2,4-dimethylvaleronitdle), 2,2-azobis (methylbutyronitrile), 1,1-azobis(cyanocyclohexane), di-t-butyl peroxide, dicumyl peroxide, t-butylcumyl peroxide, 2,5-dimethyl-2,5-bis(2-ethylhexanoyl peroxy)hexane, t-butyl peroxyneodecanote, t-butyl peroxy 2-ethylhexanoate, di(4-t-butyl cyclohexyl) peroxydicarbonate, t-butyl peroxypivalate, decanoyl peroxide, lauroyl peroxide, benzoyl peroxide, 2,4-pentanedione peroxide, di(n-propyl) peroxydicarbonate, t-amyl peroxyneodecanoate and t-butyl peroxyacetate wherein 2,2-azobis(isobutyronitrile) is preferred.

(18) Suitable ultraviolet light absorbers include for example but are not limited to beta-(4-benzotriazoyl-3-hydroxyphenoxy) ethyl acrylate, 4-(2-acryloxyethoxy)-2-hydroxybenzophenone, 4-methacryloxy-2-hydroxybenzo-phenone, 2-(2-methacryloxy-5-methylphenyl)benzotriazole, 2-(2-hydroxy-5-methacryoxyethylphenyl)-2H-benzo-triazole, 2-[3-tert-Butyl-2-hydroxy-5-(3-methacryloyloxypropyl)phenyl]-5-chlorobenzotriazole, 2-(3-tert-Butyl-5-[3-dimethylvinyisilylpropoxy)-2-hydro-xyphenyl]-5-methoxybenzotriazole, 2-(3-Allyl-2-hydroxy-5-methylphenyl)benzo-triazole, 2-[3-tert-Butyl-2-hydroxy-5-(3 methacryloyloxypropoxy)phenyl]-5-methoxybenzotriazole, and 2-[3-tert-Butyl-2-hydroxy-5-(3-methacryloyloxypropoxy)phenyl]-5-chlorobenzotriazole wherein beta-(4-benzotriazoyl-3-hydroxyphen-oxy)ethyl acrylate is the preferred ultraviolet light absorber.

(19) A UV absorber optionally may be added to the copolymer compositions. A novel, preferred, UV/blue light absorber, i.e., vinyl anthracene, may be added to the copolymer compositions. Conventional U.V. absorbers such as a vinyl benzophenone or a vinyl benzotriazole also may be used.

(20) A monomeric dye capable of copolymerizing with the hydrophobic and the hydrophilic monomers optionally may be added to the copolymer to attenuate specific 30 wavelengths of light. Such dyes include but are not limited to those containing vinyl groups and are capable of absorbing violet, blue, red, and green light in the range of 400-700 nm.

(21) Examples of such monomeric dyes include but are not limited to:

(22) Disperse Red 13 acrylate,

(23) Disperse Orange 3 acrylamide

(24) Disperse Orange 3 methacrylamide

(25) Disperse Red 1 methacrylate

(26) Disperse Red 1 acrylate

(27) Disperse Red 13 methacrylate

(28) Disperse yellow 7 acrylate

(29) Disperse yellow 7 methacrylate

(30) Ethyl trans--cyano-3-indoleacrylate

(31) [(S)-()-1-(4-Nitrophenyl)-2-pyrrolidinemethyl]acrylate

General Preparation Steps for Polymers of Examples 1-15

(32) The comonomers listed below were mixed in a glass flask using a magnetic stir bar for at least 30 minutes, at room temperature followed by sonication for the times indicated, and then stirring again for another 30 minutes. The combination of sonication and hydrophilic/hydrophobic repulsion forces allows the formation of nanoclusters. The size of the nanoclusters is theoretically controlled by the amount of energy provided during these steps. It was found that sonicating for about 30 minutes at a power setting of 100% on a Branson 5510 sonicator provides optically clear materials with adequate optical and physical properties. Sonicating time may vary between 1 minutes to 60 minutes depending on the formulation used. It has also been found that an optional second sonication step of at least about 10 minutes is sometimes needed to produce materials of the desired optical characteristics.

(33) The resulting copolymers are rigid enough to be machined at around room temperature. A unique and surprising aspect of the above materials is that the refractive index of the copolymers is so high that ophthalmic lenses can be made thin enough to be folded without further processing or hydration.

Examples 1-15

(34) TABLE-US-00001 Mono- % mer Cocentration RI EWC Processing conditions Ex. 1 VC 30 1.5690 1.5 20 minutes sonication LM 37 twice HEMA 30 EGDM 3 Ex. 2 VC 30 1.5687 1.7 25 minutes sonication LM 37 twice HEA 30 EGDM 3 Ex. 3 VC 30 1.5634 1.8 15 minutes sonication EHA 37 HEMA 30 EGDM 3 Ex. 4 VC 30 1.5623 1.7 15 minutes sonication EHA 37 HEA 30 EGDM 3 Ex. 5 VN 30 1.5541 1.7 10 minutes sonication EHA 37 HEMA 30 EGDM 3 Ex. 6 VC 30 1.5512 1.6 10 minutes sonication EHA 37 HEA 30 EGDM 3 Ex. 7 VC 25 1.5476 1.4 15 minutes sonication EHA 52 HEMA 20 EGDM 3 Ex. 8 VC 25 1.5442 1.7 15 minutes sonication EHA 52 HEA 20 EGDM 3 Ex. 9 VC 35 1.5623 1.7 10 minutes sonication EHA 47 HEMA 15 EGDM 3 Ex. 10 VC 35 1.5601 1.1 15 minutes sonication EHA 47 twice HEMA 10 EGDM 3 Preferred Formulations Ex. 11 VC 30 1.5590 1.2 30 minutes sonication EHA 42 HEMA 25 EGDM 3 Ex. 12 VC 27.5 1.5510 1.0 30 minutes sonication LM 44.0 twice HEA 25.5 EGDM 3 Ex. 13 VC 27.0 1.5500 1.0 30 minutes sonication LM 42.0 twice HEA 24.0 EGDM 0.25 VA 0.45 Ex. 14 VC 27.0 1.5511 1.0 30 minutes sonication LM 44.5 twice HEA 25.0 EGDM 2.5 DR1 0.02 Ex. 15 VC 27.0 1.5505 1.0 30 minutes sonication LM 44.5 twice HEA 25.0 EGDM 2.5 DR1 0.01 2.5% by weight of VA and 0.3% by weight of MEB was used in all copolymer compositions. VC: vinyl carbazole VN: 2-vinyl naphthalene EHA: 2-ethylhexylacrylate LM: Lauryl methacrylate HEMA; Hyroxyethylmethacrylate HEA: Hydroxyethylacrylate EGDM: ethylene glycol dimethacrylate VA: vinyl anthracene MEB: 2-(2-Methacryloxy-5methylphenyl)benzotriazole DR 1: Disperse Red 1 Methacrylate