EP4735923A1 - Blue filter combinations for ophthalmic devices - Google Patents

Blue filter combinations for ophthalmic devices

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Publication number
EP4735923A1
EP4735923A1 EP25765065.5A EP25765065A EP4735923A1 EP 4735923 A1 EP4735923 A1 EP 4735923A1 EP 25765065 A EP25765065 A EP 25765065A EP 4735923 A1 EP4735923 A1 EP 4735923A1
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Prior art keywords
meth
monomer
acrylate
group
linear
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EP25765065.5A
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German (de)
French (fr)
Inventor
Giuseppe CAROLI
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Teleon Holding BV
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Teleon Holding BV
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L33/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • C08L33/04—Homopolymers or copolymers of esters
    • C08L33/06—Homopolymers or copolymers of esters of esters containing only carbon, hydrogen and oxygen, which oxygen atoms are present only as part of the carboxyl radical
    • C08L33/08—Homopolymers or copolymers of acrylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/0008—Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
    • C08K5/0041—Optical brightening agents, organic pigments

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

The invention provides ophthalmic devices provided with improved blue filtering, mimicking the transmittance of the human ageing eye closer than hitherto possible. The invention furthermore provides methods to obtain such ophthalmic devices, as well as application thereof for prevention or treatment of a degenerative eye disease.

Description

P130724PC00
Title: Blue filter combinations for ophthalmic devices
The invention is in the field of ophthalmic devices.
INTRODUCTION
Ophthalmic devices are known devices which improve vision of (in particular) humans. A variety of different ophthalmic devices exists; in the present context, lens materials are particularly included, such as intraocular lenses or contact lenses.
One important application of ophthalmic devices is to restore vision of a human subject, in particular upon aging. With aging, the natural lenses of the human eye will accumulate pigments comprised of 3-hydroxyl kynurenine. These pigments offer protection to the retina against UV light. As aging proceeds, also the transmission of the blue light will decrease. This natural increasing filtering of the blue light will further protect the retina from the phototoxicity of lipofuscin, a phototoxic pigment that also accumulates in the aging eye, in particular in the retina, and the phototoxicity of which is induced by blue light (Sparrow JR, Nakanishi K, Parish CA, “The lipofuscin fluorophore A2E mediates blue light -induced damage to retinal pigmented epithelial cells”, Invest Ophthalmol Vis Sci, 2000; 1981-9). In fact, it has been suggested that including blue filtering features in artificial lenses can potentially prevent the development and progression of age-related macular degeneration (AMD) (Braunstein RE, Sparrow JR, “A blue-blocking intraocular lens should be used in cataract surgery”, Arch Ophthalmol, 2005).
An advantage of providing an ophthalmic device with a transmittance spectrum closely mimicking the transmittance of the human eye is that the artificial lens will mimic in the best possible manner the natural defense of the ageing eyes against high-energy (short-wavelength) visible light. Therefore, ophthalmic devices which mimic closely the (individual or average) blue light transmittance of the natural lens can be expected to prevent eye damage in the most optimal way.
Ophthalmic devices comprising blue filters have generally been known. However, known lenses generally suffered from a transmittance spectrum which did not represent the transmittance spectrum of the naturally ageing eye. As such, such lenses often altered color perception, or contributed to the development of eye diseases. The present invention overcomes these drawbacks.
FIGURES
Figure 1: transmittance spectra of monomer lb-1, monomer 2b and the combination of monomer lb-1 and monomer 2b on the basis of calculation and in a real lens, as compared to the transmittance of the human eye at ages 40 - 49 and at ages 50 - 59.
Figure 2: transmittance spectra of monomer lb-1, monomer 3b-l and the combination of monomer lb-1 and monomer 3b- 1 on the basis of calculation and in a real lens, as compared to the transmittance of the human eye at ages 40 - 49 and at ages 50 - 59.
Figure 3: transmittance spectra of the human eye at ages 40 - 49 and at ages 50 - 59.
Figure 4a: the transmittance spectra of monomer 3b-l, monomer lb-2, and of the combination of monomers 3b- 1 and lb-2.
Figure 4b: the transmittance spectra of monomer 3b-l, monomer lb-2, and the sum %T of monomers 3b- 1 and lb-2 in the presence of a UV blocker. Figure 5: the transmittance spectra of monomer 3b- 1, 1c and the sum in the presence of a UV blocker.
Figure 6: the transmittance spectra of monomer lb-2, 2b and the sum in the presence of a UV blocker.
Figure 7: the transmittance spectra of monomer 1c, 2b and lc+2b in the presence of a UV blocker. Figure 8: the transmittance spectra of monomer Id, 3b-l and ld+3b-l in the presence of a UV blocker.
Figure 9: the transmittance spectra of monomer Id, 2b and ld+2b in the presence of a UV blocker.
Figure 10: the transmittance spectra of monomer 2d, 3b-l and 2d+3b-l in the presence of a UV blocker.
Figure 11: the transmittance spectra of monomer 2b, lb-2, 3c-l and the sum of 2b+lb-2+3c-l.
Figure 12: the transmittance spectra of monomer 3c-2 and 2c in the presence of a UV blocker.
Figure 13: the transmittance spectra of monomer lb-2 and 3c- 1 in the presence of a UV blocker.
Figure 14: the transmittance spectra of monomer 3c-2 and lb-1 in the presence of a UV blocker.
Figure 15: the transmittance spectra of monomer 3c-2 and 2e in the presence of a UV blocker.
Figure 16: the transmittance spectra of monomer 3c-2, lb-2 and 3b-2 in the presence of a UV blocker.
Figure 17: the transmittance spectra of monomer 2b, 3c-l and lb-2 in the presence of a UV blocker.
Figure 18: comparison of the transmission spectrum of a prior art product (Example 8 of US 5,662,707) with the transmission spectrum of the human eye.
DETAILED DESCRIPTION
The invention is directed to an ophthalmic device comprising a copolymer of one or more (meth) acrylate monomers, said copolymer further comprising a combination of at least two (meth)acrylic azobenzene dyes onomer 2 and monomer 3:
• One of R2, R3, R9, R10 or R11 is (meth)acrylic portion o X = NR12 or O; o R1 is H or methyl;
• R2 - R11 can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms, optionally substituted with one or more R13; CF3; CH2F; CHF2; CCI3;
CH2CI; CHCI2; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR12; CO2R12 and NR122, provided that R6 is not NO2, CF3, CCI3, CBrs or CI3, and/or any two adjacent positions of R4 - R8 can be a cyclic aromatic or a cyclic non-aromatic substituent selected from Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic non-aromatic substituent is optionally substituted with one or more R12 and/or one or more R13; o R12 can be, independently, on each occurrence, H or a linear or branched alkyl group having 1 - 5 carbon atoms; o R13 can be selected, independently, on each occurrence, from the group of CF3; CH2F; CHF2; CC13; CH2C1; CHC12; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR12; CO2R12 and NR12 2; o X = NR14 or O; o R1 is H or methyl;
• R2 - R13 can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms, optionally substituted with one or more R15; CF3; CH2F; CHF2; CCI3;
CH2CI; CHCI2; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR14; CO2R14 and NR142, provided that R8 is not NO2, CF3, CCI3, CBr3 or CI3; and/or wherein any two adjacent positions of R2 - R13 can be a cyclic aromatic or a cyclic non-aromatic substituent selected from the group of Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic non- aromatic substituent is optionally substituted with one or more R14 and/or one or more R15; o R14 can be selected, independently, on each occurrence, from the group consisting of H or a linear or branched alkyl group having 1 - 5 carbon atoms; o R15 can be selected, independently, on each occurrence, from the group of CF3; CH2F; CHF2; CC13; CH2C1; CHC12; CBr3;
CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR14;
CO2R14 and NR14 2; wherein
One of R2, R3, R9, R10 or R11 is (meth)acrylic portion o X = NR12 or O; o R1 is H or methyl;
• R6 is NO2, CF3, CC13, CBr3 or CI3; • R2 - R5 and R7 - R11 can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms optionally substituted with one or more R12; CF3; CH2F; CHF2; CC13; CH2CI; CHCI2; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br;
I; CN; NO2; OR12; CO2R12 and NR122, and/or wherein any two adjacent positions of R2 - R5 and/or R7 - R11 can be a cyclic aromatic or a cyclic non-aromatic substituent selected from the group consisting of Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic non-aromatic substituent is optionally substituted with one or more R12 and/or one or more R13; o R12 can be selected, independently, on each occurrence, from the group consisting of H or a linear or branched alkyl group having 1 - 5 carbon atoms; o R13 can be selected, independently, on each occurrence, from the group of CF3; CH2F; CHF2; CC13; CH2C1; CHC12; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR12; CO2R12 and NR122.
Monomer 1, monomer 2 and monomer 3 are azobenzene dyes, modified with an acrylic or a methacrylic portion for copolymerizing into a (meth)acrylic copolymer. All of monomers 1, 2 and 3 comprise an azobenzene dye portion, and a (meth)acrylic portion. Monomer 1, monomer 2 and monomer 3 are different compounds.
Monomer 1, monomer 2 and monomer 3 can thus be referred to as different types of (meth)acrylic azobenzene dyes, having a dye portion and a (meth)acrylic portion, wherein the dye portion (the azobenzene dye portion) is coupled through an amide or ester bond to the carbonyl group of the (meth)acrylic portion. In much preferred embodiments, the dye portion of monomer 1, monomer 2 and/or monomer 3 is coupled through an amide bond to the carbonyl group of the (meth)acrylic portion (X = N). In alternative preferred embodiments, the dye portion of monomer 1, monomer 2 and/or monomer 3 is coupled through an ester bond to the carbonyl group of the (meth)acrylic portion (X = O).
The azobenzene (meth)acrylic dyes are blue filter dyes, usable in ophthalmic devices.
A blue filter is a compound that absorbs blue light, that is, light in the blue region of the visible spectrum. In preferred embodiments, a blue filter also absorbs violet light. Generally a blue filter absorbs both violet and blue light. A blue light filter in the present context thus is a compound which absorbs light in the wavelength of 250 - 550 nm, preferably 300 - 500 nm, more preferably 350 - 500 nm. Absorption, in this context, means that the transmittance of light of any wavelength within a mentioned range is less than 90 %, preferably less than 85 %, more preferably less than 81 %, even more preferably less than 75 %. The skilled person can determine the transmittance of a compound based by measuring the absorbance using common general knowledge, for example using ISO 11979-5.
The ophthalmic device of the invention comprises a (meth)acrylic copolymer, which (meth)acrylic copolymer comprises one or more acrylate and/or methacrylate monomers, and which (meth)acrylic copolymer furthermore comprises a combination of at least two (meth)acrylic azobenzene dyes selected from monomer 1, monomer 2 and monomer 3.
Said combination of at least two (meth)acrylic azobenzene dyes selected from monomer 1, monomer 2 and monomer 3 into the (meth)acrylic copolymer offers the unforeseen benefit that it allows for adapting the transmittance spectrum of the (meth)acrylic copolymer so as to mimic the transmittance spectrum of the human eye with higher accuracy than hitherto possible. By combination of the at least two monomers selected from monomer 1, monomer 2 and monomer 3 into the (meth)acrylic copolymer, it has been found possible to adapt the transmittance spectrum so as to correspond to the transmittance spectrum of the human eye at a specific age, or to adapt the transmittance spectrum to individual needs.
Monomer 1
Monomer 1 is a (meth)acrylic azobenzene dye of formula 1: o X = NR12 or O; o R1 is H or methyl;
• R2 - R11 except the (meth)acrylic portion can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms, optionally substituted with one or more R13; CF3; CH2F; CHF2; CC13; CH2C1; CHC12; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR12; CO2R12 and NR12 2, provided that R6 is not NO2, CF3, CC13, CBr3 or CI3, and/or any two adjacent positions of R4 - R8 can be a cyclic aromatic or a cyclic non-aromatic substituent selected from Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic non-aromatic substituent is optionally substituted with one or more R12 and/or one or more R13; o R12 can be, independently, on each occurrence, H or a linear or branched alkyl group having 1 - 5 carbon atoms; o R13 can be selected, independently, on each occurrence, from the group of CF3; CH2F; CHF2; CC13; CH2C1; CHC12; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR12; CO2R12 and NR122;
In preferred embodiments of monomer 1, the (meth)acrylic portion is present as R11, depicted as monomer la, with R2 - R10 as defined above for monomer 1:
In preferred embodiments of monomer 1, R2 - R11 except the (meth)acrylic portion (R2 -R10 in monomer la) can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms; CF3; CCI3; F; Cl; CN; OR12; CO2R12 and NR122, and/or any two adjacent positions of R4 - R8 can be a cyclic aromatic or a cyclic non- aromatic substituent selected from Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic nonaromatic substituent is optionally substituted with one or more R12, wherein R12 can be selected, independently, on each occurrence, from the group consisting of H or a linear or branched alkyl group having 1 - 5 carbon atoms.
In further preferred embodiments of monomer 1, R1 is H or methyl, and R2 - R11 except the (meth)acrylic portion (R2 -R10 in monomer la) can be independently selected from the group consisting of H, a linear or branched alkyl group having 1 - 5 carbon atoms, OR12 or CO2R12, wherein R12 can be H or a linear or branched alkyl group having 1 - 5 carbon atoms, wherein preferably X is NR12, R12 preferably being H, and wherein further preferably, all of R2 - R11 except the (meth)acrylic portion (R2 -R10 in monomer la) is H.
In other preferred embodiments of monomer 1, R11 is the (meth)acrylic portion, R6 is NR122 and the remainder of R2 - R11 is H, or R11 is the (meth)acrylic portion, R2 and/or R4 and/or R8 and/or R10 are a linear or branched alkyl group having 1 - 5 carbon atoms, preferably methyl, and the remainder of R2 - R11 is H, or R11 is the (meth) acrylic portion and the remainder of R2 - R11 is H.
In much preferred embodiments, monomer 1 is monomer lb, depicted as: wherein R1 = H or methyl, and wherein X = N or O. Preferably, X = N. Alternatively preferred is the case where X = O. In further preferred embodiments, monomer 1 is monomer 1c, depicted as: wherein R1 = H or methyl, and wherein X = N or O, preferably O.
In further preferred embodiments, monomer 1 is monomer Id, depicted as: wherein R1 = H or methyl, and wherein X = N or O, preferably N.
Monomers of formula 1 can be obtained by starting from an appropriate azobenzene dye portion, which is generally commercially available. In cases where the azobenzene dye portion is not commercially available, the person skilled in the art of organic chemistry can synthesize the azobenzene dye portion based on common general knowledge.
An azobenzene dye portion thus obtained can be substituted with an acrylic or a methacrylic portion by for example amide or ester synthesis, or other appropriate reactions from the synthetic organic chemistry toolbox.
Monomer 1 is preferably present in the (meth)acrylic copolymer in a concentration of 0.01 - 0.5 wt.%, preferably 0.02 - 0.35 wt.%, more preferably 0.03 - 0.25 wt.%, relative to the quantity of all monomers for incorporation in the (meth)acrylic copolymer which are not azobenzene dyes of formulae 1, 2 or 3.
Monomer 2
Monomer 2 is a (meth)acrylic azobenzene dye of formula 2: o X = NR14 or O, preferably NR14; alternatively preferred OR14; o R1 is H or methyl;
• R2 - R13 except the (meth)acrylic portion can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms, optionally substituted with one or more R15; CF3; CH2F; CHF2; CC13; CH2C1; CHC12; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR14; CO2R14 and NR14 2, provided that R8 is not NO2, CF3, CC13, CBr3 or CI3, and/or wherein any two adjacent positions of R2 - R13 except the (meth)acrylic portion can be a cyclic aromatic or a cyclic non-aromatic substituent selected from the group of Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic non-aromatic substituent is optionally substituted with one or more R14 and/or one or more R15; o R14 can be selected, independently, on each occurrence, from the group consisting of H or a linear or branched alkyl group having 1 - 5 carbon atoms; o R15 can be selected, independently, on each occurrence, from the group of CF3; CH2F; CHF2; CC13; CH2C1; CHC12; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR14; CO2R14 and NRi42.
In preferred embodiments of monomer 2, the (meth)acrylic portion is present as R11 or as R13. Monomer 2 wherein the (meth)acrylic portion is present as R13 is depicted as monomer 2a, with R2 - R12 as defined above for monomer 2:
In preferred embodiments of monomer 2, R2 - R13 except the (meth)acrylic portion (R2 - R12in monomer 2a) can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms; CF3; CCI3; F; Cl; CN; OR14; CO2R14 and NR142, and/or wherein any two adjacent positions of R2 - R13 except the (meth)acrylic portion (R2 - R12in monomer 2a), preferably any two adjacent positions of R2 - R5, alternatively or additionally of R6 - R10, alternatively or additionally of R11 - R13 (R11 - R12 in monomer 2a), can be a cyclic aromatic or a cyclic non-aromatic substituent selected from the group of Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic non-aromatic substituent is optionally substituted with one or more R14.
In further preferred embodiments, R1 is H or methyl, and the (meth)acrylic portion is present as R11 or as R13, wherein if the methacrylic portion is present R13, preferably X = NR14, with R14 preferably being H, and wherein if the (meth)acrylic portion is present as R11, preferably X = O; and/or wherein further preferably, all of R2 - R13 except the (meth)acrylic portion is H and/or a linear branched or cyclic group which may be saturated, unsaturated or aromatic, consisting of only 1 - 5 carbon atoms and hydrogen atoms.
In preferred embodiments, monomer 2 is monomer 2b: wherein X = N or O, preferably N, and wherein R1 = H or methyl.
In further preferred embodiments, monomer 2 is monomer 2c:
wherein X = N or O, preferably O, and wherein R1 = H or methyl.
In further preferred embodiments, monomer 2 is monomer 2d: wherein X= N or O, preferably O, and wherein R1 = H or methyl.
In further preferred embodiments, monomer 2 is monomer 2e: wherein X=N or O, preferably O, and wherein R1 = H or methyl.
Monomers of formula 2 can be obtained by starting from an appropriate azobenzene dye portion, which is generally commercially available. In cases where the azobenzene dye portion is not commercially available, the person skilled in the art of organic chemistry can synthesize the azobenzene dye portion based on common general knowledge. An azobenzene dye portion thus obtained can be substituted with an acrylic or a methacrylic portion by for example amide or ester synthesis, or other appropriate reactions from the synthetic organic chemistry toolbox.
Monomer 2 is preferably present in the (meth)acrylic copolymer in a concentration of 0.005 - 0.5 wt.%, preferably 0.01 - 0.35 wt.%, preferably 0.02 - 0.25 wt.%, more preferably 0.03 - 0.15 wt.%, relative to the quantity of all monomers for incorporation in the (meth)acrylic copolymer which are not azobenzene dyes of formulae 1, 2 or 3.
Monomer 3
Monomer 3 is a (meth)acrylic azobenzene dye of formula 3: o X = NR12 or O, preferably NR12; o R1 is H or methyl;
• R6 is NO2, CF3, CCI3, CBr3 or CI3, preferably NO2, CF3, CCI3, more preferably NO2;
• R2 - R5 and R7 - R11, except the (meth)acrylic portion, can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms optionally substituted with one or more R13; CF3; CH2F; CHF2; CCI3; CH2CI; CHCI2; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR12; CO2R12 and NR122, and/or wherein any two adjacent positions of R2 - R5 and/or R7 - R11 except the (meth)acrylic portion can be a cyclic aromatic or a cyclic non-aromatic substituent selected from the group consisting of Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic non- aromatic substituent is optionally substituted with one or more R12 and/or one or more R13; o R12 can be selected, independently, on each occurrence, from the group consisting of H or a linear or branched alkyl group having 1 - 5 carbon atoms; o R13 can be selected, independently, on each occurrence, from the group of CF3; CH2F; CHF2; CC13; CH2C1; CHC12; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR12; CO2R12 and NR122.
In preferred embodiments of monomer 3, the (meth)acrylic portion is present as R11, depicted as monomer 3a, with R2 - R10 as defined above for monomer 3:
In preferred embodiments, R2 - R5 and R7 - R11 except the (meth)acrylic portion (R2 - R5 and R7 - R10 in monomer 3a) can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms; CF3; CCI3; F; Cl; CN; OR12; CO2R12 and NR122, and/or wherein any two adjacent positions of R2 - R5 and/or R7 - R11 except the (meth)acrylic portion (R2 - R5 and R7 - R10 in monomer 3a) can be a cyclic aromatic or a cyclic non-aromatic substituent selected from the group consisting of Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic non-aromatic substituent is optionally substituted with one or more R12.
In further preferred embodiments, R1 is H or methyl, and R6 is NO2, CF3 or CCI3, preferably NO2, and R2 - R5 and R7 - R11 except the (meth)acrylic portion (R2 - R5 and R7 - R10 in monomer 3a) can be independently selected from the group consisting of H, a linear or branched alkyl group having 1 - 5 carbon atoms, OR12 or CO2R12, wherein R12 can be H or a linear or branched alkyl group having 1 - 5 carbon atoms, wherein preferably X is NR12, with R12 preferably being H, and wherein further preferably, all of R2 - R5 and R7 - R11 except the (meth)acrylic portion (R2 - R5 and R7 - R10 in monomer 3a) are H. In much preferred embodiments, monomer 3 is monomer 3b, depicted as: wherein X = N or O, and wherein R1 is H or methyl. In one preferred embodiment, X = N. In this embodiment, preferably R1 = H. In another preferred embodiment, X = O. In this embodiment, preferably R 1 = methyl.
In further preferred embodiments, monomer 3 can be monomer
3c, depicted as: o X is NR12 or O, preferably NR12; o R1 is H or methyl;
• and wherein the other of R1 can be H or methyl.
Monomers of formula 3 can be obtained by starting from the appropriate azobenzene dye portion, which is generally commercially available. In cases where the appropriate azobenzene dye portion is not commercially available, the person skilled in the art of organic chemistry can synthesize the azobenzene dye portion based on common general knowledge.
An azobenzene dye portion thus obtained can be substituted with an acrylic or a methacrylic portion by for example amide or ester synthesis, or other appropriate reactions from the synthetic organic chemistry toolbox.
Monomer 3 is preferably present in the (meth)acrylic copolymer in a concentration of 0.005 - 0.5 wt.%, preferably 0.01 - 0.45 wt.%, more preferably 0.015 - 0.40 wt.%, more preferably 0.02 - 0.35 wt.%, relative to the quantity of all monomers for incorporation in the (meth)acrylic copolymer which are not azobenzene dyes of formulae 1, 2 or 3.
At least two monomers selected from monomers 1 - 3
The ophthalmic device of the invention comprises in the (meth)acrylic copolymer at least two different monomers selected from monomer 1, monomer 2 and monomer 3. That is, the ophthalmic device of the invention comprises a first (meth)acrylic azobenzene dye selected from one of the groups of formula 1, 2 and 3, and further comprises at least one second, different (meth)acrylic azobenzene dye selected from one of the groups of formula 1, 2 and 3, wherein the group from which the first (meth) acrylic dye was selected is different from the group from which the second (meth)acrylic dyes was selected.
Any combination of monomers may be used, such as monomer 1 + monomer 2, monomer 1 + monomer 3, monomer 2 + monomer 3, or monomer 1 + monomer 2 + monomer 3.
Preferably, the (meth)acrylic copolymer comprises a combination of monomer 1 and monomer 2. Alternatively, the (meth)acrylic copolymer preferably comprises a combination of monomer 1 and monomer 3. Further alternatively, the (meth)acrylic copolymer preferably comprises a combination of monomer 2 and monomer 3. In particularly preferred embodiments, the (meth)acrylic copolymer comprises a combination of monomer lb, preferably lb-1 and monomer 2b, as herein defined.
Further preferably, the (meth)acrylic copolymer comprises a combination of monomer lb, preferably lb-1 or alternatively lb-2, and monomer 3b, preferably 3b- 1, as herein defined.
Further preferably, the (meth)acrylic copolymer comprises a combination of monomer 1c and monomer 3b, preferably 3b- 1, as herein defined.
Further preferably, the (meth)acrylic copolymer comprises a combination of monomer lb, preferably lb-2, and monomer 2b, as herein defined.
Further preferably, the (meth)acrylic copolymer comprises a combination of monomer 1c and monomer 2b, as herein defined.
Further preferably, the (meth)acrylic copolymer comprises a combination of monomer Id and monomer 3b, preferably 3b- 1, as herein defined.
Further preferably, the (meth)acrylic copolymer comprises a combination of monomer Id and monomer 2b, as herein defined.
Further preferably, the (meth)acrylic copolymer comprises a combination of monomer 2d and monomer 3b, preferably 3b- 1, as herein defined.
In some embodiments, the (meth)acrylic copolymer comprises 2 or more different (meth)acrylic azobenzene dyes falling under the scope of formula 1. In such embodiments, 2, 3, 4, 5, 6 or even more different azobenzene (meth)acrylic dyes falling under the scope of formula 1 may be used. Likewise, the (meth)acrylic copolymer may comprise 2 or more different (meth)acrylic azobenzene dyes falling under the scope of formula 2, and/or falling under the scope of formula 3. In such embodiments, 2, 3, 4, 5, 6 or even more different (meth)acrylic azobenzene dyes falling under the scope of formula 2 and/or formula 3 may be used.
In preferred embodiments, one or more (preferably one) of the group of lb-1, lb-2, 1c and Id is combined with either one or more (preferably one) of the group of 2b, 2c, 2d and 2e, or with one or more (preferably one) of the group of 3b- 1, 3b-2, 3c- 1 and 3c-2, or both (as listed in table 2 below).
In further preferred embodiments, one or more (preferably one) of the group of 2b, 2c, 2d and 2e is combined with either one or more (preferably one) of the group of lb-1, lb-2, 1c and Id, or with one or more of the group of 3b- 1, 3b-2, 3c- 1 and 3c-2 (preferably one), or both (as listed in table 2 below).
In further preferred embodiments, the combination comprises at least 2 compounds, a first compound having been selected from one of the groups of monomer 1 (as defined above on the basis of formula 1, preferably lb-1, lb-2, 1c and Id), monomer 2 (as defined above on the basis of formula 2, preferably 2b, 2c, 2d and 2e) and monomer 3 (as defined above on the basis of formula 3, preferably (3b-l, 3b-2, 3c-l and 3c-2), and the second compound having been selected from another of the groups of monomer 1 (as defined above on the basis of formula 1, preferably lb-1, lb-2, 1c and Id), monomer 2 (as defined above on the basis of formula 2, preferably 2b, 2c, 2d and 2e) and monomer 3 (as defined above on the basis of formula 3, preferably (3b- 1, 3b-2, 3c- 1 and 3c-2), wherein any third or further compound can be selected from any of the groups of monomer 1 (preferably lb-1, lb-2, 1c and Id), monomer 2 (preferably 2b, 2c, 2d and 2e) and monomer 3 (preferably (3b- 1, 3b-2, 3c- 1 and 3c-2).
In much preferred embodiments, the combination of monomers 1, 2 and 3 is as listed in the figures and/or in the examples (without the specific UV-blocker; in preferred embodiments, a UV-blocker can be present, as elsewhere described). According to the present invention, the total of all one or more compounds falling under the definition of monomer 1, 2 or 3 is to be combined with the total of all one or more compounds falling under the definition of the other monomer(s).
Furthermore, the (meth)acrylic copolymer used in the ophthalmic device of the invention may comprise further colorants, not falling under the scope of any of formula 1, formula 2 or formula 3, provided the (meth)acrylic copolymer comprises at least two monomers selected from monomer 1, monomer 2 and monomer 3.
In preferred embodiment, the (meth)acrylic copolymer furthermore comprises a UV-blocker. A UV-blocker is a (meth)acrylic monomer which provides strong absorption of UV-light. A UV-blockers is a (meth)acrylic monomer which provides more than 90 % transmission at wavelengths above 375 nm, preferably above 400 nm, more preferably above 425 nm. The skilled person knows from common general knowledge which (meth)acrylic monomers can be considered a UV-blocker, in the present context of ophthalmic devices.
In much preferred embodiments, the UV-blocker is a (meth)acrylic dye which at least absorbs UV light in the range of 200 - 450 nm, preferably 250 - 425 nm, more preferably 250 - 375 nm. Absorption, in this regard, means that the transmittance of the dye in a wavelength range is less than 90 %, more preferably less than 80 %, more preferably less than 70 %, more preferably less than 60 %.
The (meth)acrylic copolymer, and ophthalmic devices prepared therefrom
The composition of the (meth)acrylic copolymer is expressed by reference to the percentage by weight of the monomers included into the copolymer, excluding the (meth)acrylic azobenzene dyes of formula 1, 2 and 3 (monomers 1, 2 and 3). For example, a (meth)acrylic copolymer described as comprising 20 wt.% X and 80 wt.% Y refers to a (meth)acrylic copolymer prepared from 20 wt.% monomer X and 80 wt.% monomer Y, the weight percentages of monomer X and monomer Y expressed as wt.% relative to the total mixture of monomers used to obtain the (meth)acrylic copolymer, excluding the (meth)acrylic azobenzene dyes of formula 1, 2 and 3. That is, the total of the transparent monomers for inclusion into the copolymer, combined with any quantity of (for example) a UV-blocker, but without the quantity of all compounds of formula 1, 2 and 3.
The (meth)acrylic copolymer preferably comprises (“is prepared from”) at least 80 wt.%, preferably at least 90 wt.%, more preferably at least 95 wt.%, even more preferably at least 99 wt.% of (meth) acrylate monomers. A (meth)acrylate monomer, in this context, refers to any monomer which is suitable for inclusion into a (meth) acrylic copolymer for use in ophthalmic devices, having a (meth)acrylic portion. Said (meth)acrylic monomers are preferably transparent, at least after polymerization of the copolymer.
In some specific embodiments, the (meth)acrylic copolymer may comprise other, non (meth)acrylate monomers, in a quantity preferably not exceeding 20 wt.%, more preferably not exceeding 10 wt.%, more preferably not exceeding 5 wt.%, more preferably not exceeding 1 wt.%. Non (meth)acrylate monomers in this regard comprise in particular vinyl monomers.
In preferred embodiments, the (meth)acrylic copolymer comprises at least 80 wt.%, preferably at least 90 wt.%, more preferably at least 95 wt.%, of transparent (meth)acrylate monomers. Transparent (meth)acrylate monomers, in this context, are (meth) acrylate monomers which after polymerization into the (meth)acrylic copolymer do not contribute to light absorption in the visible spectrum, i.e. from 400 - 900 nm. That is, a transparent (meth) acrylate monomer in the present context is a (meth)acrylate monomer which on its own, after polymerization, displays more than 80 % transmittance, preferably more than 85 % transmittance, more preferably more than 90 % transmittance, most preferably more than 95 % transmittance in the visible spectrum.
Preferred transparent (meth)acrylate monomers can be selected from the group consisting of methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, butyl (meth)acrylate, isobornyl (meth)acrylate, dodecyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, phenyl (meth)acrylate, benzyl (meth)acrylate, 2-phenylethyl (meth)acrylate, 2 -phenoxy ethyl (meth)acrylate, ethylene glycol di(meth)acrylate, tetra (ethylene glycol) di(meth)acrylate, trimethylol propane tri(meth)acrylate, tri(ethylene glycol) di(meth)acrylate, and hydroxyethyl (meth)acrylate.
In much preferred embodiments, the (meth)acrylic copolymer comprises (meth) acrylate monomers selected from the group of methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, butyl (meth)acrylate, isobornyl (meth)acrylate, dodecyl (meth)acrylate, 2- ethylhexyl (meth)acrylate, phenyl (meth)acrylate, benzyl (meth)acrylate, 2- phenylethyl (meth)acrylate, 2 -phenoxy ethyl (meth)acrylate, ethylene glycol di(meth)acrylate, tetra (ethylene glycol) di(meth)acrylate, trimethylol propane tri(meth)acrylate, tri(ethylene glycol) di(meth)acrylate, and hydroxyethyl (meth)acrylate. In much preferred embodiment, the (meth)acrylic copolymer comprises at least 80 wt.%, preferably at least 90 wt.%, more preferably at least 95 wt.% of the said group of (meth)acrylate monomers.
Monomer 1, monomer 2 and monomer 3 defined above represent further (meth)acrylic monomers from which the (meth)acrylic copolymer is prepared. The quantity of monomer 1, monomer 2 and monomer 3 in the (meth)acrylic copolymer is expressed relative to the total quantity of monomers for incorporation in the (meth)acrylic copolymer, excluding the quantities of monomers 1, 2 and 3, in weight % (wt.%).
The total quantity of monomers 1, 2 and 3 in the (meth)acrylic copolymer is at most 2.0 wt.%, preferably at most 1.5 wt.%, preferably at most 1 wt.%, more preferably at most 0.75 wt.%, relative to the quantity of all monomers for incorporation in the (meth)acrylic copolymer which are not azobenzene dyes of formulae 1, 2 or 3.
In much preferred embodiments, the total of monomer 1, monomer 2 and monomer 3 in the (meth)acrylic copolymer is at most 2.0 wt.%, such as 0.01 - 2.0 wt.%, relative to the quantity of all monomers for incorporation in the (meth)acrylic copolymer which are not azobenzene dyes of formulae 1, 2 or 3.
In further preferred embodiments, the total of monomer 1, monomer 2 and monomer 3 in the (meth)acrylic copolymer is at most 1.5 wt.%, such as 0.02 - 1.5 wt.%, relative to the quantity of all monomers for incorporation in the (meth)acrylic copolymer which are not azobenzene dyes of formulae 1, 2 or 3.
In further preferred embodiments, the total of monomer 1, monomer 2 and monomer 3 in the (meth)acrylic copolymer is at most 1.35 wt.%, such as 0.03 - 1.35 wt.%, relative to the quantity of all monomers for incorporation in the (meth)acrylic copolymer which are not azobenzene dyes of formulae 1, 2 or 3.
In further preferred embodiments, the total of monomer 1, monomer 2 and monomer 3 in the (meth)acrylic copolymer is at most 1.0 wt.%, such as 0.04 - 1.0 wt.%, relative to the quantity of all monomers for incorporation in the (meth)acrylic copolymer which are not azobenzene dyes of formulae 1, 2 or 3.
In further preferred embodiments, the total of monomer 1, monomer 2 and monomer 3 in the (meth)acrylic copolymer is at most 0.75 wt.%, such as 0.05 - 0.75 wt.%, relative to the quantity of all monomers for incorporation in the (meth)acrylic copolymer which are not azobenzene dyes of formulae 1, 2 or 3.
In further preferred embodiments, the total of monomer 1, monomer 2 and monomer 3 in the (meth)acrylic copolymer is at most 0.65 wt.%, such as 0.06 - 0.65 wt.%, relative to the quantity of all monomers for incorporation in the (meth)acrylic copolymer which are not azobenzene dyes of formulae 1, 2 or 3.
The (meth)acrylic copolymer can be prepared by polymerization, among which by cationic, anionic or radical polymerization, as is known in the art, and as further detailed below.
In preferred embodiments, the (meth)acrylic copolymer is prepared by radical polymerization. Preferred polymerization initiators, for use in preparing the present (meth)acrylic copolymer, include a diazo-initiator, such as 2,2-azobis(2,4-dimethylvaleronitrile) and/or azobisisobutyronitrile, an organic peroxide, such as di-t-butyl peroxide, benzoyl peroxide or methyl ethyl ketone peroxide, or a photo-initiator, such as phenylbis(2,4,6- trimethylbenzoyl)phosphine oxide.
The (meth)acrylic copolymer defined herein, as well as ophthalmic devices prepared from said (meth)acrylic copolymer, have the advantage that they can be prepared to mimic the transmittance spectrum of the human eye more closely than hitherto possible. By combining at least two different (meth)acrylic monomers selected from (different groups of) monomer 1, monomer 2 and monomer 3 as described, the transmittance spectrum in the blue region of the visible spectrum can be tailored to any desired transmittance spectrum, in particular the transmittance spectrum of the human eye. This is because the transmittance of the two or more blue filters selected from monomers 1, 2 and 3 which are present, collectively provide for the transmittance spectrum of the (meth)acrylic copolymer (or, in turn, of the ophthalmic device prepared therefrom). By changing the relative concentration of the at least two monomers selected from monomers 1, 2 and 3, the combined transmittance spectrum of the at least two monomers can be tailored to specific needs, in particular in the blue region of the spectrum, i.e. in the region of 375 - 500 nm, preferably 400 - 500 nm, more preferably 425 - 495 nm. A desired transmittance spectrum can be the transmittance spectrum of the human eye as defined by Artigas (IOVS, June 2012, Vol 53, No 7, pg 4076 - 4084). A much desired transmittance spectrum is the average transmittance spectrum of the human eye in the age group of 40 - 49 years, as defined by Artigas, in the age group of from 50 - 59 years, as defined by Artigas, or in the age group of 40 - 59 years, as derivable from Artigas. This can be achieved by combining at least two (meth)acrylic monomers selected from monomer 1, monomer 2 and monomer 3 as described above, preferably in the quantities given above.
An ophthalmic device as herein described can prevent, delay or halt a degenerative eye disease, such as in particular age-related macular disease (AMD). The invention thus furthermore provides a method for preventing, delaying or halting a degenerative eye disease, in particular age-related macular disease, comprising a step of contacting the ophthalmic device herein defined with a human eye.
For the exemplary case of a combination of monomer 1 and monomer 2 in an ophthalmic device prepared from a (meth)acrylic copolymer as defined above, the weight ratio between monomer 1 and monomer 2 (monomer 1 : monomer 2) is preferably s - 5 : 1, more preferably 1 - 3 : 1, even more preferably 1.2 - 1.8 : 1.
For the alternative exemplary case of a combination of monomer 1 and monomer 3 in an ophthalmic device prepared from an acrylic polymer as defined above, the weight ratio between monomer 1 and monomer 3 (monomer 1 : monomer 3) is preferably 1 - 10 : 1, preferably 1.5 - 6 : 1, more preferably 1.8 - 2.5 : 1.
A further much preferred transmittance spectrum can be a transmittance spectrum as defined by an optometrist. By allowing an optometrist, or another expert at eye functioning, to define a specific transmittance spectrum, individual problems may be addressed. For example, such adaptation of the light transmission spectrum of the optical material for an ophthalmic device may facilitate higher contrast sensitivity of the human eye, see for example, Hammond (Hammond et al, “The Effects of Blue Light-Filtering Intraocular Lenses on the Protection and Function of the Visual System”, Clin Ophthalmol. 2019;13:2427-2438).
The present invention allows to obtain ophthalmic devices with blue light filtering according to any specific, individual need. This provides advantages for example in the field of personalized medicine, where individual needs, rather than averaged solutions, have preference.
Ophthalmic devices which may be prepared from the (meth)acrylic copolymer described herein include an intraocular lens, a contact lens, or any other ophthalmic device with optical functionality. Preferably, the ophthalmic device is an intraocular lens (IOL).
Thus, the invention furthermore provides an ophthalmic device as defined above, preferably an intraocular lens, for use in preventing, delaying or halting a degenerative eye disease, preferably the treatment of age- related macular disease (AMD). The invention also provides a combination of at least two different monomers selected from (different classes of) monomer 1, monomer 2 and monomer 3 above for use in the preventing, delaying or halting a degenerative eye disease, preferably the treatment of age-related macular disease (AMD). The invention also provides use of a combination of at least two different monomers selected from (different classes of) monomer 1, monomer 2 and monomer 3 above, for the manufacture of a medicament for preventing, delaying or halting a degenerative eye disease, preferably for the treatment of age-related macular disease (AMD). Treatment, in this regard, preferably comprises a step of surgically implanting the ophthalmic device defined above into a human eye in need of said treatment.
The invention furthermore provides a method for preventing, delaying or halting a degenerative eye disease, comprising a step of contacting the ophthalmic device defined above with a human eye. Preferably, the method slows or halts the onset of age-related macular disease (AMD). Further preferably, said method comprises a step of surgically implanting the ophthalmic device defined above into a human eye in need of said treatment.
The invention also discloses a polymerizable composition, comprising the monomers defined above, preferably in the quantities defined above.
Methods for making the (meth)acrylic copolymer
The invention furthermore provides methods to prepare the (meth)acrylic copolymer, and to prepare an ophthalmic device therefrom. In one aspect, the invention provides a method for making an ophthalmic copolymer, or an ophthalmic device, comprising a. preparing a mixture of the monomers defined above; b. initiating polymerization; c. allowing polymerization of the mixture of monomers to obtain an ophthalmic copolymer; d. Optionally, performing an extraction to remove side products and/or residual unreacted monomer from the ophthalmic copolymer.
The ophthalmic copolymer can be used as an ophthalmic device as such, in situations where the ophthalmic copolymer is prepared in a suitable mold in order to have an appropriate shape, which is known in the art.
The ophthalmic copolymer may also be subjected to further treatment, as is known in the art, in order to obtain the ophthalmic device. Such further treatment may include a step of lathing, milling, molding and/or polishing of the ophthalmic copolymer in order to gain an appropriate shape. The mixture of monomers is preferably a homogenously mixed monomer mixture. Said mixture is preferably liquid. Furthermore, said mixture is preferably stirred.
Initiating polymerization preferably comprises addition of a radical polymerization initiator, preferably a diazo-initiator, such as 2,2-azobis(2,4- dimethylvaleronitrile) and/or azobisisobutyronitrile. Alternatively, an organic peroxide, such as di-t-butyl peroxide, benzoyl peroxide or methyl ethyl ketone peroxide, or a photo-initiator, such as phenylbis(2,4,6- trimethylbenzoyl)phosphine oxide, can be used. The skilled person knows how to initiate and sustain polymerization of the present mixture of monomers, based on common general knowledge.
Polymerization of the mixture of monomers provides the ophthalmic copolymer. In some embodiments, the ophthalmic copolymer is subsequently subjected to an extraction to remove side products and/or residual unreacted monomer from the ophthalmic copolymer. In some embodiments, the ophthalmic copolymer is subsequently subjected to a step of shaping the ophthalmic copolymer into an ophthalmic device, such as by lathing, milling, molding and/or polishing.
EXAMPLES
Methodology
Transmittance
Transmittance was determined by UV/Vis spectrophotometry. The sample was a finished IOL hydrated in a 0.9% sodium chloride water solution. The transmittance was measured according to ISO 11979-5.
Preparation of ophthalmic devices
An ophthalmic device (in casu: an intraocular lens) was prepared by preparing a mixture of monomers and initiator (in casu: AIBN) as indicated in the below examples, in the indicated quantities. The mixture was stirred at room temperature. Subsequently, the mixture was used to fill the desired molds, and polymerization was allowed to proceed by increasing the temperature to 95 °C for 3 hours.
Example 1: combination of blue filters to mimic the transmittance spectrum of the human eye.
A (meth)acrylate monomer mixture of the composition described in table 1 was prepared, and monomers lb-1, 2b and a combination of lb-1 and 2b were added in quantity of 0.057 (lb-1) and 0.039 (2b) wt.%, relative to the total quantity of monomers listed above. For the (meth)acrylate azobenzene dye structures, see table 2 below.
The mixture was supplied with an initiator (AIBN, 0.5 wt.%), and stirred until all the solid components were completely dissolved. Next, the mixture was used to fill molds of appropriate design (optical disks, blanks to be lathed in a next step, or rods to be sliced to obtain blanks in a next step), and thermally cured at 95 °C for three hours. The obtained (meth)acrylic copolymer was demolded, and machined to obtain finished IOLS. The obtained IOLs were hydrated in demineralized water for 1 day, and then their UV/Vis spectrum was recorded according to ISO 11979-5 to obtain the transmission spectra (see fig. 1).
Table 1: exemplary composition of a (meth)acrylic copolymer, as used in Example 1. component weight %
Butyl methacrylate 74.2
Di(ethylene glycol)ethylether acrylate 21.6
Tri (propylene glycole) diacrylate 4.2
Total monomers 100 Example 2: combination of blue filters to mimic the transmittance spectrum of the human eve
Example 2 is identical to example 1, except that a different combination of (meth)acrylic azobenzene dyes was used: monomer lb-1 (0.057 wt.%) and monomer 3b- 1 (0.026 wt.%).
Example 3: combination of blue filters to mimic the transmittance spectrum of the human eve
To support the principle that the transmittance spectrum of the combination of blue filters of the present invention can be tailored to mimic the desired transmittance spectrum of the human eye, further examples are provided here.
The (meth)acrylic azobenzene dyes were prepared from commercially obtained azobenzene dyes having a free amino- or hydroxy group in the appropriate position, to provide the azobenzene dye portion of the (meth)acrylic azobenzene dyes. The azobenzene dyes were coupled to (meth)acrylic acid by first converting the (meth) acrylic acid to the corresponding acid chloride using oxalyl chloride in DMF. Subsequently, the acid chloride was reacted with the free amino- or hydroxy substituted azobenzene dye to obtain monomer 1, 2 or 3. Pure (meth)acrylic azobenzene dyes were obtained, using column chromatography where needed to get pure compounds.
Combinations of at least two different monomers selected from monomer 1, 2 and 3 were used to provide a transmittance which closely mimics the transmission of the human eye. As an exemplary combination, the transmittance spectra of monomer 3b-l, monomer lb-2 and of the combination (3b-l)+(lb-2) is shown in Figure 4. In Figure 4a, the transmittance of only lb-2, 3b- 1 and (3b-l)+(lb-2) is shown, whereas in Figure 4B, there is an additional UV blocker present (CAS 2170-39-0); the summed transmittance represents the combined transmittance of lb-2, 3b- 1 and the UV-blocker. It can be seen that the combination of monomer lb-2 with monomer 3b- 1 closely mimics the transmittance of the human eye, regardless of the presence or absence of a UV blocker.
Further examples are shown in Figures 5 - 11, for combinations of at least two of monomers 1, 2 and 3, in combination with a UV-blocker (CAS 2170- 39-0):
• Monomer 1c and 3b- 1 (Figure 5)
• Monomer lb-2 and 2b (Figure 6)
• Monomer 1c and 2b (Figure 7)
• Monomer Id and 3b- 1 (Figure 8)
• Monomer Id and 2b (Figure 9)
• Monomer 2d and 3b- 1 (Figure 10)
• Monomer 2b, lb-2 and 3c- 1 (Figure 11)
• Monomer 3c-2 and 2c (Figure 12)
• Monomer lb-2 and 3c- 1 (Figure 13)
• Monomer 3c-2 and lb-1 (Figure 14)
• Monomer 3c-2 and 2e (Figure 15)
• Monomer 3c-2, lb-2 and 3b-2 (Figure 16)
• Monomer 2b, 3c- 1 and lb-2 (Figure 17)
Example 4: comparison with prior art products
The transmittance spectrum of example 8 in US 5,662,707 has been reproduced and plotted against the transmittance spectrum of the human eye, in line with all previous examples (Figure 18). It can be seen from the figure that the transmittance spectrum of this prior art product deviates considerably further from the transmittance spectrum of the human eye, than any of the combinations disclosed herein.

Claims

Claims
1. An ophthalmic device comprising a copolymer of one or more (meth)acrylate monomers, said copolymer further comprising at least two (meth)acrylic monomers selected from monomer 1, monomer 2 and monomer
3: wherein
One of R2, R3, R9, R10 or R11 is a (meth)acrylic portion o X is NR12 or O; o R1 is H or methyl;
• R2 - R11 can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms, optionally substituted with one or more R13; CF3; CH2F; CHF2; CCI3;
CH2CI; CHCI2; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR12; CO2R12 and NR122, provided that R6 is not NO2, CF3, CCI3, CBrs or CI3, and/or any two adjacent positions of R4 - R8 can be a cyclic aromatic or a cyclic non-aromatic substituent selected from Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic non-aromatic substituent is optionally substituted with one or more R12 and/or one or more R13 o R12 can be, independently, on each occurrence, H or a linear or branched alkyl group having 1 - 5 carbon atoms o R13 can be selected, independently, on each occurrence, from the group of CF3; CH2F; CHF2; CC13; CH2C1; CHC12; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR12; CO2R12 and NR12 2; o X is NR14 or O; o R1 is H or methyl;
• R2 - R13 can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms, optionally substituted with one or more R15; CF3; CH2F; CHF2; CC13;
CH2C1; CHC12; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR14; CO2R14 and NR14 2, provided that R8 is not NO2, CF3, CC13, CBr3 or CI3, and/or wherein any two adjacent positions of R2 - R13 can be a cyclic aromatic or a cyclic non-aromatic substituent selected from the group of Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic nonaromatic substituent is optionally substituted with one or more R14 and/or one or more R15; o R14 can be selected, independently, on each occurrence, from the group consisting of H or a linear or branched alkyl group having 1 - 5 carbon atoms; o R15 can be selected, independently, on each occurrence, from the group of CF3; CH2F; CHF2; CC13; CH2C1; CHC12; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR14; CO2R14 and NRi4 2; wherein
R1
One of R2, R3, R9, R10 or R11 is a (meth)acrylic portion o X is NR12 or O; o R1 is H or methyl;
• R6 is NO2, CF3, CC13, CBr3 or CI3;
• R2 - R5 and R7 - R11 can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms optionally substituted with one or more R12; CF3; CH2F; CHF2; CC13; CH2CI; CHCI2; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br;
I; CN; NO2; OR12; CO2R12 and NR122, and/or wherein any two adjacent positions of R2 - R5 and/or R7 - R11 can be a cyclic aromatic or a cyclic non-aromatic substituent selected from the group consisting of Cl - C5 cycloalkyl; Cl - C4 alkylene dioxy; phenyl; and an aromatic five or six membered heterocycle comprising one or more N, S and/or O heteroatoms, which cyclic aromatic or cyclic non-aromatic substituent is optionally substituted with one or more R12 and/or one or more R13; o R12 can be selected, independently, on each occurrence, from the group consisting of H or a linear or branched alkyl group having 1 - 5 carbon atoms; o R13 can be selected, independently, on each occurrence, from the group of CF3; CH2F; CHF2; CC13; CH2C1; CHC12; CBr3; CH2Br; CHBr2; CI3; CH2I; CHI2; F; Cl; Br; I; CN; NO2; OR12; CO2R12 and NR122.
2. An ophthalmic device according to claim 1, wherein the copolymer comprises
• at least one monomer 1 and at least one monomer 2; or
• at least one monomer 1 and at least one monomer 3; or
• at least one monomer 2 and at least one monomer 3; or
• at least one monomer 1 and at least one monomer 2 and at least one monomer 3.
3. An ophthalmic device according to claim 1 or 2, wherein
• monomer 1 is a compound of formula 1 wherein R1 is H or methyl, and wherein R2 - R11 can be independently selected from the group consisting of H; a linear or branched alkyl group having 1 - 5 carbon atoms, preferably methyl; NR122, OR12 or CO2R12, preferably NR122; wherein R12 can be H or a linear or branched alkyl group having 1 - 5 carbon atoms, wherein preferably, the (meth)acrylic portion is present as R11, and/or wherein further preferably X = NR12, with R12 preferably being H, and/or wherein further preferably, all of R2 - R11 except the (meth)acrylic portion is H and/or NR122 and/or methyl, most preferably R11 is the (meth)acrylic portion, R6 is NR122 and the remainder of R2 - R11 is H, or R11 is the (meth)acrylic portion, R2 and/or R4 and/or R8 and/or R10 are a linear or branched alkyl group having 1 - 5 carbon atoms, preferably methyl, and the remainder of R2 - R11 is H, or R11 is the (meth)acrylic portion and the remainder of R2 - R11 is H; and/or
• monomer 2 is a compound of formula 2 wherein R1 is H or methyl, and wherein R2 - R13 can be independently selected from the group consisting of H, a linear, branched or cyclic group having 1 - 5 carbon atoms, OR14 or CO2R14, wherein R14 can be H or a linear or branched alkyl group having 1 - 5 carbon atoms which linear, branched or cyclic group may be saturated, unsaturated or aromatic, wherein preferably the (meth)acrylic portion is present as R11 or as R13, wherein if the (meth)acrylic portion is present R13, preferably X = NR14, with R14 preferably being H, and wherein if the (meth)acrylic portion is present as R11, preferably X = O; and/or wherein further preferably, all of R2 - R13 except the (meth)acrylic portion is H and/or a linear branched or cyclic group which may be saturated, unsaturated or aromatic, consisting of only 1 - 5 carbon atoms and hydrogen atoms; and/or
• monomer 3 is a compound of formula 3 wherein R1 is H or methyl, wherein R6 is NO2, CF3 or CCI3, preferably NO2, and wherein R2 - R5 and R7 - R11 can be independently selected from the group consisting of H, a linear or branched alkyl group having 1 - 5 carbon atoms, OR12 or CO2R12, wherein R12 can be H or a linear or branched alkyl group having 1 - 5 carbon atoms, wherein preferably, the (meth)acrylic portion is present as R11, and/or wherein further preferably X = NR12, with R12 preferably being H, and/or wherein further preferably, all of R2 - R5 and R7 - R11 except the (meth)acrylic portion is H.
4. An ophthalmic device according to any of claims 1 - 3, wherein the one or more (meth)acrylate monomers comprise (meth)acrylate monomers selected from the group of methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, butyl (meth)acrylate, isobornyl (meth)acrylate, dodecyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, phenyl (meth)acrylate, benzyl (meth)acrylate, 2-phenylethyl (meth)acrylate, 2 -phenoxy ethyl (meth)acrylate, ethylene glycol di(meth)acrylate, tetra (ethylene glycol) di(meth)acrylate, trimethylol propane tri(meth)acrylate, tri(ethylene glycol) di(meth)acrylate, and hydroxyethyl (meth)acrylate.
5. An ophthalmic device according to any of claims 1 - 4, wherein the concentration of monomer 1 is 0.01 - 0.5 wt.%, preferably 0.02 - 0.35 wt.%, more preferably 0.03 - 0.25 wt.%, and/or wherein the concentration of monomer 2 is 0.005 - 0.5 wt.%, preferably 0.01 - 0.35 wt.%, more preferably 0.02 - 0.25 wt.%, and/or wherein the concentration of monomer 3 is 0.005 - 0.5 wt.%, preferably 0.01 - 0.45 wt.%, more preferably 0.015 - 0.40 wt.%, more preferably 0.02 - 0.35 wt.%, all quantities being expressed relative to the quantity of all monomers for incorporation in the ophthalmic device which are not monomers of formulae 1, 2 or 3.
6. An ophthalmic device according to any of claims 1 - 5, wherein the ophthalmic device is an intraocular lens.
7. A polymerizable composition, comprising the monomers defined in any of claims 1 - 5.
8. A method for making an ophthalmic device, comprising a. preparing a mixture of the monomers defined in any of claims 1-5; b. initiating polymerization; c. allowing polymerization of the mixture of monomers to obtain an ophthalmic copolymer; d. Optionally, performing an extraction to remove side products and/or residual unreacted monomer from the ophthalmic copolymer.
9. A method for making an ophthalmic device according to claim 8, wherein initiating polymerization comprises addition of a radical polymerization initiator, preferably a diazo-initiator, such as 2,2-azobis(2,4- dimethylvaleronitrile) and/or azobisisobutyronitrile, an organic peroxide, such as di-t-butyl peroxide, benzoyl peroxide or methyl ethyl ketone peroxide, or a photo-initiator, such as phenylbis(2,4,6- trimethylbenzoyl)phosphine oxide.
10. A method for making an ophthalmic device according to claims 8 or 9, further comprising a step of lathing, molding and/or polishing of the ophthalmic device.
11. A method for preventing, delaying or halting a degenerative eye disease, comprising a step of contacting the ophthalmic device according to any of claims 1 - 6 with a human eye.
12. A method according to claim 11, wherein the method slows or halts the onset of age-related macular disease (AMD), said method comprising a step of surgically implanting the ophthalmic device of claim 6 into a human eye in need of said treatment.
13. An ophthalmic device according to any of claims 1 - 6 for use in preventing, delaying or halting a degenerative eye disease, preferably age- related macular disease (AMD).
EP25765065.5A 2024-09-05 2025-09-04 Blue filter combinations for ophthalmic devices Pending EP4735923A1 (en)

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Publication number Priority date Publication date Assignee Title
US5470932A (en) 1993-10-18 1995-11-28 Alcon Laboratories, Inc. Polymerizable yellow dyes and their use in opthalmic lenses
SG11201406978RA (en) * 2012-04-27 2015-01-29 Kowa Co Stable polymerizable uv-absorbing colorant for intraocular lens
US11958824B2 (en) * 2019-06-28 2024-04-16 Johnson & Johnson Vision Care, Inc. Photostable mimics of macular pigment

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