Intraocular lens composition
阅读说明：本技术 人工晶体组合物 (Intraocular lens composition ) 是由 G·卡洛里 B·万德斯 于 2020-03-06 设计创作，主要内容包括：本发明涉及包含单体的聚合物混合物的人工晶体组合物、包含该组合物的产品及其用途。本发明的组合物完全不含液泡,因此产生了真正的不含闪亮部的材料。此外,其足够柔软从而易于折叠,具有适当的调谐硬度来提供舒适的展开速度,需要低注射力,不存在禁止的粘性,并且具有良好的光学性质。最后,本人工晶体组合物不会遭遇钙化。(The present invention relates to an intraocular lens composition comprising a polymer mixture of monomers, products comprising the composition and uses thereof. The composition of the invention is completely free of vacuoles and therefore produces a material that is truly free of sparkles. In addition, it is flexible enough to fold easily, has a suitable tuned stiffness to provide a comfortable deployment speed, requires low injection force, is free of prohibitive stickiness, and has good optical properties. Finally, the present intraocular lens composition does not suffer from calcification.)
1. An intraocular lens composition comprising a polymer mixture of monomers comprising:
a short crosslinker comprising two or more (meth) acrylate moieties and a linking moiety located between the two (meth) acrylate moieties, the linking moiety being connected to the (meth) acrylate moieties through an ester group, wherein the longest linear atomic sequence between the oxygen atom of the ester group connecting the first (meth) acrylate moiety to the linking moiety and the oxygen atom of the ester group connecting the second (meth) acrylate moiety to the linking moiety is from 1 to 11 atoms;
a long crosslinker comprising two or more (meth) acrylate moieties and a linking moiety located between the two (meth) acrylate moieties, the linking moiety being connected to the (meth) acrylate moieties through an ester group, wherein the longest linear atomic sequence between an oxygen atom of the ester group connecting a first (meth) acrylate moiety to the linking moiety and an oxygen atom of the ester group connecting a second (meth) acrylate moiety to the linking moiety is 12 atoms or more;
one or more (meth) acrylate monomers of formula (I):
wherein:
x is- (C1-C4 alkyl) -O-, - (C1-C4 alkyl) -S-, - (C1-C4 alkyl) -N-or C1-C8 alkyl, wherein C1-C8 alkyl comprises cycloalkyl and one C atom is substituted by a heteroatom selected from O, S and N;
y is absent or-C1-C4 alkyl;
n is 1 to 6;
r is H or CH 3;
one or more C1-C4-alkyl (meth) acrylate monomers of formula (II):
wherein:
y is-C1-C4 alkyl;
r is H or CH 3;
or a combination of at least one phenyl C1-C4-alkyl (meth) acrylate of formula (III) and at least one cycloalkyl (meth) acrylate of formula (IV):
wherein:
x is absent or is-C1-C4 alkyl;
r is H or CH 3;
wherein:
x is absent and is C1-C5 alkyl or- [ (C1-C4 alkyl) -O]n-, where n is 1 to 8;
y is a C3-C18 alkyl group comprising at least one cycloalkyl moiety, wherein the C3-C18 alkyl group optionally comprises one or more heteroatoms selected from O and N groups;
r is H or CH 3.
2. The intraocular lens composition of claim 1, wherein the longest linear sequence of atoms defined by the long and short cross-linkers comprises C, O, and N atoms, wherein the total number of C atoms exceeds the total number of O and N atoms, and wherein the linear sequence of atoms comprises atoms selected from R2、OR2、SR2、NR2 2、COOR2Or a pendant group of F, wherein R2Is H, alkyl, cycloalkyl, heterocycloalkyl, an aromatic moiety or any combination thereof, R2Has a molecular weight of at most 100 Da.
3. The intraocular lens composition of claim 1 or 2, wherein the amount of short crosslinker is from 0.1 to 12 wt.%, and/or the amount of long crosslinker is from 0.5 to 25 wt.%, and/or the amount of one or more (meth) acrylate monomers of formula (I) is from 10 to 90 wt.%, and/or the amount of one or more C1-C4-alkyl (meth) acrylate monomers of formula (II) or the combination of phenyl-C1-C4-alkyl (meth) acrylate of formula (III) and cycloalkyl (meth) acrylate of formula (IV) is from 5 to 70 wt.%, based on the total monomer mixture.
4. The intraocular lens composition of any one of claims 1 to 3, wherein the short cross-linking agent comprises ethylene glycol di (meth) acrylate, or trimethylolpropane tri (meth) acrylate, or tetra (ethylene glycol) di (meth) acrylate, or di (ethylene glycol) di (meth) acrylate, or tri (propylene glycol) di (meth) acrylate, or tri (ethylene glycol) di (meth) acrylate.
5. The intraocular lens composition of any one of claims 1-4, wherein the long cross-linking agent comprises poly (ethylene glycol) di (meth) acrylate or poly (propylene glycol) di (meth) acrylate.
6. The intraocular lens composition of any one of claims 1-5, wherein the one or more (meth) acrylate monomers of formula (I) comprise: di (ethylene glycol) ethyl ether acrylate, or 2-methoxyethyl methacrylate, or di (ethylene glycol) methyl ether methacrylate, or tetrahydrofurfuryl acrylate, or triethylene glycol methyl ether methacrylate, or mixtures thereof.
7. The intraocular lens composition of any one of claims 1 to 6, wherein the one or more C1-C4-alkyl (meth) acrylate monomers of formula (II) comprise: butyl methacrylate, or ethyl methacrylate, or propyl methacrylate, or tert-butyl acrylate, or methyl methacrylate, or phenyl-C1-C4-alkyl (meth) acrylates of the formula (III) include: phenyl methacrylate, or benzyl acrylate, or benzyl methacrylate, or 2-phenylethyl acrylate, or 2-phenylethyl methacrylate, and the cycloalkyl (meth) acrylate of formula (IV) includes: cyclohexyl acrylate, isobornyl methacrylate, cyclohexyl methacrylate, 1-adamantyl methacrylate, or isobornyl methacrylate.
8. The intraocular lens composition of any one of claims 1 to 7, comprising a polymer mixture of:
(a)
5-40% by weight of phenyl methacrylate, preferably 22. + -. 5% by weight
10-55% by weight of cyclohexyl acrylate, preferably 29. + -. 5% by weight
15-55% by weight of di (ethylene glycol) ethyl ether acrylate, preferably 38. + -.5% by weight
1-20% by weight of a poly (ethylene glycol) diacrylate having a molecular weight of 250-5000Da, preferably 400-1000Da, preferably 7. + -. 5% by weight
2-10% by weight of trimethylolpropane triacrylate, preferably 4. + -.2% by weight
Or (b)
5-80% by weight of butyl methacrylate, preferably 68. + -. 5% by weight
3-45% by weight of di (ethylene glycol) ethyl ether acrylate, preferably 20. + -.5% by weight
1-15% by weight of a poly (ethylene glycol) diacrylate having a molecular weight of 250-1800Da, preferably 400-1000Da, preferably 8. + -. 5% by weight
0.1 to 8% by weight of tri (propylene glycol) diacrylate, preferably 4. + -. 2% by weight
Or (c)
5-65% by weight of benzyl acrylate, preferably 16. + -. 5% by weight
5-75% by weight of isobornyl methacrylate, preferably 30. + -. 5% by weight
15-80% by weight of di (ethylene glycol) ethyl ether acrylate, preferably 45. + -.5% by weight
1-15% by weight of poly (ethylene glycol) dimethacrylate with a molecular weight of 250-5000Da, preferably 400-2500Da, preferably 6. + -. 5% by weight
0.1 to 8% by weight of ethylene glycol dimethacrylate, preferably 4. + -. 2% by weight
Or (d)
1-60% by weight of ethyl methacrylate, preferably 30. + -. 5% by weight
3 to 75% by weight of methoxyethyl acrylate and/or 2 to 85% by weight of methoxyethyl methacrylate, preferably 52. + -. 5% by weight of methoxyethyl acrylate and 9. + -. 5% by weight of methoxyethyl methacrylate
1-15% by weight of a poly (ethylene glycol) diacrylate having a molecular weight of 200-5000Da, preferably 200-1000Da, preferably 5. + -. 2% by weight
0.1 to 8% by weight of ethylene glycol dimethacrylate, preferably 5. + -. 2% by weight
Or (e)
5-75% by weight of benzyl methacrylate, preferably 31. + -.5% by weight
25-75% by weight of cyclohexyl acrylate, preferably 15. + -. 5% by weight
15-80% by weight of di (ethylene glycol) methyl ether methacrylate, preferably 48. + -.5% by weight
1-15% by weight of poly (ethylene glycol) dimethacrylate with a molecular weight of 250-5000Da, preferably 400-1600Da, preferably 4. + -. 2% by weight
0.1 to 8% by weight of trimethylolpropane triacrylate, preferably 2. + -. 1% by weight
Or (f)
1-65% by weight of propyl methacrylate, preferably 22. + -. 5% by weight
5-85% by weight of 2- (2-methoxyethoxy) ethyl methacrylate, preferably 70. + -.5% by weight
1-15% by weight of a poly (propylene glycol) diacrylate having a molecular weight of 230-2000Da, preferably 400-1600Da, preferably 5. + -. 2% by weight
0.1 to 8% by weight of trimethylolpropane trimethacrylate, preferably 3. + -. 2% by weight
Or (g)
1-55% by weight of 2-phenylethyl acrylate, preferably 10. + -. 5% by weight
3-65% by weight of cyclohexyl methacrylate, preferably 33. + -. 5% by weight
15-90% by weight of 2-methoxyethyl acrylate, preferably 45. + -.5% by weight
1-15% by weight of a poly (ethylene glycol) diacrylate having a molecular weight of 200-5000Da, preferably 200-1600Da, preferably 8. + -. 5% by weight
0.1 to 8% by weight of ethylene glycol dimethacrylate, preferably 4. + -. 2% by weight
Or (h)
From 1 to 70% by weight of tert-butyl acrylate, preferably 52. + -. 5% by weight
3-75% by weight of tetrahydrofurfuryl acrylate, preferably 35. + -.5% by weight
1-15% by weight of a poly (ethylene glycol) diacrylate having a molecular weight of 200-2000Da, preferably 400-1000Da, preferably 9. + -. 5% by weight
0.1 to 8% by weight of triethylene glycol dimethacrylate, preferably 3. + -. 2% by weight
Or (i)
From 1 to 55% by weight of benzyl acrylate, preferably 17. + -.5% by weight
2-45% by weight of 1-adamantane esters of methacrylic acid, preferably 25. + -.5% by weight
15 to 80% by weight of triethylene glycol methyl ether methacrylate and/or 2 to 45% by weight of 2-ethoxyethyl methacrylate, preferably 37. + -. 5% by weight of triethylene glycol methyl ether methacrylate and 17. + -. 5% by weight of 2-ethoxyethyl methacrylate
1-15% by weight of a poly (ethylene glycol) diacrylate having a molecular weight of 200-5000Da, preferably 200-1600Da, preferably 3. + -. 2% by weight
0.1 to 8% by weight of trimethylolpropane triacrylate, preferably 3. + -.2% by weight
Or (j)
1-75% by weight of ethyl methacrylate, preferably 22. + -. 5% by weight
2-75% by weight of 2-methoxyethyl acrylate and/or 2-75% by weight of 2-ethoxyethyl methacrylate, preferably 23. + -. 5% by weight of 2-methoxyethyl acrylate and 44. + -. 5% by weight of 2-ethoxyethyl methacrylate
1-15% by weight of poly (ethylene glycol) dimethacrylate having a molecular weight of 200-2000Da, preferably 200-1000Da, preferably 9. + -. 5% by weight
0.1 to 8% by weight of tetra (ethylene glycol) dimethacrylate, preferably 2. + -. 1% by weight
Or (k)
1-55% by weight of 2-phenylethyl methacrylate, preferably 27. + -.5% by weight
2-55% by weight of isobornyl methacrylate, preferably 14. + -. 5% by weight
15-80% by weight of 2-methoxyethyl acrylate, preferably 48. + -.5% by weight
1-15% by weight of a poly (ethylene glycol) diacrylate having a molecular weight of 200-5000Da, preferably 200-1600Da, preferably 7. + -. 5% by weight
0.1 to 8% by weight of ethylene glycol dimethacrylate, preferably 4. + -. 2% by weight
Or (l)
1-65% by weight of methyl methacrylate, preferably 27. + -. 5% by weight
10-85% by weight of 2- (2-methoxyethoxy) ethyl methacrylate, preferably 65. + -.5% by weight
1-15% by weight of a poly (propylene glycol) diacrylate having a molecular weight of 230-2000Da, preferably 400-1500Da, preferably 4. + -. 2% by weight
0.1 to 8% by weight of tetra (ethylene glycol) diacrylate, preferably 4. + -. 2% by weight
Or (m)
1-55% by weight of 2-phenylethyl acrylate, preferably 8. + -. 5% by weight
2-45% by weight of 1-adamantane esters of methacrylic acid, preferably 30. + -.5% by weight
5-80% by weight of 2-methoxyethyl acrylate and/or 2-75% by weight of di (ethylene glycol) ethyl ether acrylate, preferably 16. + -. 5% by weight of 2-methoxyethyl acrylate and 35. + -. 5% by weight of di (ethylene glycol) ethyl ether acrylate
1-15% by weight of poly (ethylene glycol) dimethacrylate with a molecular weight of 200-5000Da, preferably 200-1600Da, preferably 8. + -. 5% by weight
0.1 to 8% by weight of diethylene glycol dimethacrylate, preferably 3. + -. 2% by weight.
9. The intraocular lens composition of any one of claims 1-8, further comprising: an amount of UV light in said mixture that is suitable for absorbing at least 50% of light irradiation having a wavelength of 350nm to 400nm, preferably benzotriazole substituted methacrylate; and/or an amount of blue light filtering chromophore, said amount being adapted to absorb at least 50% of light irradiation having a wavelength of 400nm to 500 nm.
10. The intraocular lens composition of any one of claims 1-9, having a water absorption of less than 10% by weight, as measured by weight.
11. Use of an intraocular lens composition according to any one of claims 1 to 10 as a foldable implantable ophthalmic device in the treatment of cataracts and refractive surgery.
12. An intraocular lens, an artificial cornea, a corneal ring, a corneal implant, or a corneal inlay comprising the intraocular lens composition of any one of claims 1 to 10.
13. A method of making the intraocular lens composition of any one of claims 1-10, the method comprising the steps of:
1) preparing a monomer mixture according to any one of claims 1 to 10;
2) preferably, a free radical polymerization initiator is added;
3) allowing polymerization of the monomer mixture;
4) optionally, extraction is performed to remove any by-products and/or residual unreacted monomers.
14. The process according to claim 13, wherein the polymerization is carried out in an oxygen-containing atmosphere, preferably in air.
15. The method of claim 13, wherein the polymerization is carried out in an inert atmosphere.
16. The process according to any one of claims 13 to 15, wherein the radical polymerization initiator is a diazo initiator, preferably 2, 2-azobis (2, 4-dimethylvaleronitrile) and/or azobisisobutyronitrile, or the radical polymerization initiator is an organic peroxide, preferably di-tert-butyl peroxide, benzoyl peroxide or methyl ethyl ketone peroxide, or the radical polymerization initiator is a photoinitiator, such as phenylbis (2,4, 6-trimethylbenzoyl) phosphine oxide.
Background
The present invention relates to the field of intraocular lens compositions.
An intraocular lens (lenticula len) is a lens (len) that can be implanted into the eye to replace or assist the natural lens material in providing visual function. Intraocular lenses may be implanted in the eye in cases such as cataract treatment or myopia treatment.
Cataracts can affect the natural lens of the eye, causing it to become cloudy and thus blurred. In this case, the natural lens can be replaced with an intraocular lens to restore vision. Other conditions, such as myopia, can be treated by placing an intraocular lens on the natural lens, thereby altering the optical power of the eye.
Intraocular lens materials are known and there are many varieties commercially or experimentally. Typically, the intraocular lens material is a polymeric composition of one or more monomers. Important features of the material are clarity and stability. An important aspect of stability is the tendency of the lens material to form vacuoles (vacuoles) over time. The vacuole is a small inclusion inside the polymer lens material, containing water, commonly referred to as a glitter (glistening). Due to the difference in refractive index between the lens material and the water within the vacuole, the incident light will diffract, thereby creating glare (glare) and thus reducing vision.
In addition, the intraocular lens material must be sufficiently flexible to allow the lens to fold. This is important during surgery, where the lens is implanted into the eye by folding and placing it in a cartridge, and then injected into the eye through a small incision through a nozzle; finally, once in the eye, the lens will unfold and return to its original shape. However, the material should not be too soft to avoid too rapid unfolding of the lens. Deployment time is an important feature of lens material because waiting too long for the lens to deploy during surgery is inefficient and can lead to complications, but deploying the lens too quickly can cause damage to eye tissue. The viscosity of the material should be low so as not to interfere with the deployment of the lens in the eye after injection. The material must be non-brittle and able to withstand the stresses generated during injection, where the lens will be folded and pushed through a small injector nozzle of about 2mm, or the lens may break into two or more fragments or deform during injection. Finally, the lens requires a high optical quality even after the lens is injected and returns to its original shape.
Intraocular lens materials are typically either hydrophobic or hydrophilic. Hydrophilic materials have the advantage that they do not contain many vacuoles, but the material has the disadvantage that it often suffers calcification, which makes it unusable after an unpredictable period of time. Hydrophobic materials are better in this respect because they do not encounter calcification, but hydrophobic materials have a tendency to form vacuoles. This results in the lens material shining more and more over time. Furthermore, hydrophobic lens materials are generally more tacky, which can lead to complications during the deployment process, as tackiness can prevent lens deployment or haptic feedback portions from sticking to the optic (optic). Many known hydrophobic lens materials are made of harder materials to reduce glare and reduce stickiness, but harder lens materials also unfold more slowly, which affects the efficiency of the procedure, are more difficult to inject, and may even lead to nozzle rupture during surgery.
The present invention improves upon known lens materials by providing an intraocular lens composition that is completely free of vacuoles, thereby resulting in a material that is truly free of glistenings. Furthermore, it is flexible enough to fold easily, has a suitable tuned stiffness to provide a comfortable deployment speed, requires low injection forces, is free of prohibitive tack (prohibitive tack), and has good optical properties. Finally, the present intraocular lens composition does not suffer from calcification.
Drawings
FIG. 1: lenses from example 1, at 20 and 100 times magnification.
FIG. 2: lenses from example 2, at 20 and 100 times magnification.
FIG. 3: lenses from example 3, at 20 and 100 times magnification.
FIG. 4: lenses from example 4, at 20 and 100 times magnification.
FIG. 5: lenses from example 5, at 20 and 100 times magnification.
FIG. 6: lenses from example 6, at 20 and 100 times magnification.
FIG. 7: lenses from example 7, at 20 and 100 times magnification.
FIG. 8: the lenses from example 8, at 20 and 100 times magnification.
FIG. 9: lenses from example 9, at 20 and 100 times magnification.
FIG. 10: the lenses from example 10, at 20 and 100 times magnification.
FIG. 11: the lenses from example 11, at 20 and 100 times magnification.
FIG. 12: the lens from example 12, at 20 and 100 times magnification.
FIG. 13: the lens from example 13, at 20 and 100 times magnification.
FIG. 14: alcon AcrySof lens, 20 and 100 times magnification.
FIG. 15: hoya 255 lens, 20 and 100 times magnification.
FIG. 16: avansee lens, 20 and 100 times magnification.
FIG. 17: tecnis lens, 20 and 100 times magnification.
FIG. 18: asquelio lens, 20 and 100 times magnification.
FIG. 19: a model known as "flying saucer" (flying saucer).
FIG. 20: the lens from example 19, at 20 and 100 times magnification.
FIG. 21: lenses from example 20, at 20 and 100 times magnification.
Detailed Description
The invention is defined in claim 1. The present invention provides an intraocular lens composition comprising a polymer mixture of at least four different monomers as follows: a short (meth) acrylate crosslinker, a long (meth) acrylate crosslinker, one or more (meth) acrylate monomers of formula (I), and one or more C1-C4-alkyl (meth) acrylates, or a combination of phenyl-C1-C4-alkyl (meth) acrylates and cycloalkyl (meth) acrylates.
The compositions of the invention have the following advantages over known compositions: it provides an intraocular lens composition that is completely free of vacuoles, thus yielding a material that is truly free of glistenings. In addition, it is flexible enough to fold easily, has a suitable tuned stiffness to provide a comfortable deployment speed, requires low injection force, is free of prohibitive stickiness, and has good optical properties. Finally, the present intraocular lens composition does not suffer from calcification.
The intraocular lens composition may be abbreviated as an IOL. It is a polymeric intraocular lens composition based on at least the above-mentioned monomers, suitably polymerized. In a preferred embodiment, the polymer composition comprises at least 50% by weight, based on the weight of the composition, of the above monomers suitably polymerized. In a preferred embodiment, the polymer composition comprises at least 60 wt.%, preferably at least 70 wt.%, more preferably at least 80 wt.% of the above monomers, suitably polymerized.
The term "polymer mixture of monomers" (polymeric mixtures of monomers) is to be construed as known in the art and means that the monomers comprised in the polymeric intraocular lens composition have been polymerized to provide the intraocular lens composition of the present invention. In this case, polymerization means that at least 90%, typically more than 95%, typically substantially all monomer molecules (e.g., at least 99% of all monomer molecules) have undergone polymerization to produce a polymeric intraocular lens composition. If the total content of residues of unreacted monomers is higher than desired, extraction with a suitable solvent may optionally be carried out to eliminate the unreacted monomers, as is well known in the art.
Thus, a polymer mixture of monomers (which is an intraocular lens composition) is a polymer composition, which preferably contains no monomers to a large extent; in contrast, all of the monomers used have been incorporated into the polymer mixture during the polymerization reaction in preparing the intraocular lens composition. The polymer mixture of monomers contains to a large extent no unreacted monomers.
The intraocular lens composition comprises a polymer blend of monomers and may also include other conventional elements (e.g., UV and/or blue light filtering monomers) as described in WO1995/011279A 1.
In some preferred embodiments, the intraocular lens composition consists only of the polymer mixture, but may contain unavoidable impurities (e.g., impurities derived from the polymerization process, most notably impurities and degradation products derived from the polymerization initiator).
The base monomer contained in the polymer composition is a (meth) acrylate monomer. Therefore, the polymerization process to obtain the intraocular lens composition must be adapted to allow polymerization of the (meth) acrylate monomer. In a preferred embodiment, the polymerization process is a free radical polymerization process. Free radical polymerization is well known in the art.
Short cross-linking agents
The first base monomer included in the intraocular lens composition is a short crosslinking agent comprising two or more (meth) acrylate moieties and a linking moiety located between the two (meth) acrylate moieties, the linking moiety being linked to the (meth) acrylate moieties by an ester group, wherein the longest linear atomic sequence between an oxygen atom of the ester group linking the first (meth) acrylate moiety to the linking moiety and an oxygen atom of the ester group linking the second (meth) acrylate moiety to the linking moiety is from 1 to 11 atoms. The short cross-linking agent may be represented by the formula:
in the formula, R is H or CH3And SC denotes a short connection portion.
The (meth) acrylate moiety of the short crosslinker can independently be an acrylate moiety or a methacrylate moiety. In a preferred embodiment, the short crosslinker comprises two acrylate moieties or two methacrylate moieties. Most preferably, the short crosslinker comprises two methacrylate moieties (dimethacrylates).
The linking moiety is linked to the (meth) acrylate moiety of the short crosslinker through an ester group located on the carbonyl group of the (meth) acrylate.
A linking moiety is defined as a moiety that connects two (meth) acrylate moieties through a covalently bonded sequence of atoms. The longest linear atomic sequence of the short crosslinker extends between the oxygen atom of the ester group connecting the first (meth) acrylate moiety to the linking moiety and the oxygen atom of the ester group connecting the second (meth) acrylate moiety to the linking moiety and is 1 to 11 atoms, preferably 1 to 8 atoms, more preferably 2 to 5 atoms. Thus, short linking moieties are represented by linear sequences of 1 to 11, 1 to 8, or 2 to 5 atoms.
The longest linear sequence of atoms of the short cross-linking agent includes C atoms and optionally O atoms and/or N atoms, wherein the total number of C atoms exceeds the total number of O and N atoms. In a preferred embodiment, the longest linear sequence of atoms of the short crosslinker comprises only C atoms and optionally O atoms, wherein the total number of C atoms exceeds the total number of O atoms (if present). In a more preferred embodiment, the ratio of C to O is greater than 2: 1.
The longest linear atomic sequence of the short crosslinker can include a pendant group that does not significantly affect the reactivity of the (meth) acrylate portion of the short crosslinker during polymerization. Preferably, the pendant group is selected from the group consisting of: r2、OR2、SR2、NR2 2、COOR2Or F, wherein R2Is H, alkyl, cycloalkyl, heterocycloalkyl, an aromatic moiety, or any combination thereof, wherein R is2Has a molecular weight of at most 100 Da.
The short crosslinker may also comprise more than two (meth) acrylate moieties, for example three or four or more (meth) acrylate moieties.
In a more preferred embodiment, the short cross-linking agent is ethylene glycol di (meth) acrylate, propylene glycol di (meth) acrylate, butylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, dipropylene glycol di (meth) acrylate, dibutylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, tripropylene glycol di (meth) acrylate, tetraethylene glycol di (meth) acrylate, trimethylolpropane tri (meth) acrylate (trimethlpropanetri (meth) acrylate), trimethylolpropane ethoxylated tri (meth) acrylate (up to 1 unit ethoxylate per arm), trimethylolpropane propoxylated tri (meth) acrylate (up to 1 unit propoxylate per arm), glycerol tri (meth) acrylate, pentaerythritol tri (meth) acrylate, ethoxylated glycerol tri (meth) acrylate (up to 1 unit ethoxylate per arm), propoxylated glycerol tri (meth) acrylate (up to 1 unit propoxylate per arm), ethoxylated pentaerythritol tetra (meth) acrylate (up to 1 unit ethoxylate per arm), propoxylated pentaerythritol tetra (meth) acrylate (up to 1 unit propoxylate per arm), ditrimethylolpropane tetra (meth) acrylate, pentaerythritol tetra (meth) acrylate, dipentaerythritol penta (meth) acrylate, or dipentaerythritol hexa (meth) acrylate, preferably ethylene glycol di (meth) acrylate, propylene glycol di (meth) acrylate, butylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, dipropylene glycol di (meth) acrylate, propylene glycol di (meth) acrylate, propylene glycol (meth) acrylate, propylene glycol acrylate, propylene, Dibutylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, tripropylene glycol di (meth) acrylate, tetraethylene glycol di (meth) acrylate, trimethylolpropane tri (meth) acrylate, glycerol tri (meth) acrylate, pentaerythritol tri (meth) acrylate, ditrimethylolpropane tetra (meth) acrylate, pentaerythritol tetra (meth) acrylate, dipentaerythritol penta (meth) acrylate, or dipentaerythritol hexa (meth) acrylate, more preferably ethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, trimethylolpropane tri (meth) acrylate, propylene glycol di (meth) acrylate, tripropylene glycol di (meth) acrylate, tetraethylene glycol di (meth) acrylate, ditrimethylolpropane tetra (meth) acrylate or pentaerythritol tetra (meth) acrylate. In some embodiments, acrylates are preferred. In an alternative preferred embodiment, methacrylates are preferred.
Preferably, the amount of short-chain crosslinker in the monomer mixture is from 0.1 to 12% by weight, preferably from 0.2 to 10% by weight, more preferably from 0.5 to 8% by weight, based on the total amount of monomer mixture.
In some more preferred embodiments, the amount of short-chain crosslinker in the monomer mixture is from 0.1 to 3 wt.%, preferably from 0.1 to 2 wt.%. In other more preferred embodiments, the amount of short-chain crosslinker in the monomer mixture is from 2 to 10 wt.%, preferably from 2 to 7 wt.%.
Long crosslinking agent
The second base monomer included in the intraocular lens composition is a long cross-linking agent comprising two or more (meth) acrylate moieties and a linking moiety located between the two (meth) acrylate moieties, the linking moiety being linked to the (meth) acrylate moieties by an ester group, wherein the longest linear atomic sequence between an oxygen atom of the ester group linking the first (meth) acrylate moiety to the linking moiety and an oxygen atom of the ester group linking the second (meth) acrylate moiety to the linking moiety is 14 atoms or more. The long crosslinking agent may be represented by the formula:
in the formula, R is H or CH3And LC represents a long connecting portion.
The (meth) acrylate moiety of the long crosslinker may independently be an acrylate moiety or a methacrylate moiety. In a preferred embodiment, the long crosslinker comprises two acrylate moieties or two methacrylate moieties.
The linking moiety is linked to the (meth) acrylate moiety of the long crosslinker through an ester group that is located on the carbonyl group of the (meth) acrylate.
A linking moiety is defined as a moiety that connects two (meth) acrylate moieties through a covalently bonded sequence of atoms. The longest linear atomic sequence of the long crosslinker linking moiety extends between the oxygen atom of the ester group linking the first (meth) acrylate moiety to the linking moiety and the oxygen atom of the ester group linking the second (meth) acrylate moiety to the linking moiety and is 12 atoms or more, preferably at least 15 atoms, more preferably at least 20 atoms. In a preferred embodiment, the longest linear atomic sequence of the long crosslinker is at most 100 atoms, preferably at most 80 atoms, more preferably at most 50 atoms, for example, at most 30 atoms.
The longest linear sequence of atoms of the long crosslinker includes C atoms and optionally O atoms and/or N atoms, wherein the total number of C atoms exceeds the total number of O and N atoms. In a preferred embodiment, the longest linear sequence of atoms of the long crosslinker includes only C atoms and optionally O atoms, wherein the total number of C atoms exceeds the total number of O atoms (if present). In a more preferred embodiment, the ratio of C to O is greater than 2: 1.
The longest linear atomic sequence of the long crosslinker can include a pendant group that does not significantly affect the reactivity of the (meth) acrylate portion of the long crosslinker during polymerization. Preferably, the pendant group is selected from the group consisting of: r2、OR2、SR2、NR2 2、COOR2Or F, wherein R2Is H, alkyl, cycloalkyl, heterocycloalkyl, an aromatic moiety, or any combination thereof, wherein R is2Has a molecular weight of at most 100 Da.
The long crosslinker may also comprise more than two (meth) acrylate moieties, for example three or four or more (meth) acrylate moieties. The long crosslinker may be referred to as a "star" long crosslinker.
In a more preferred embodiment, the long crosslinking agent is poly (ethylene glycol) di (meth) acrylate, poly (propylene glycol) di (meth) acrylate, poly (butylene glycol) di (meth) acrylate, poly (pentylene glycol) di (meth) acrylate, trimethylolpropane ethoxylate tri (meth) acrylate (having sufficient ethoxylation units to form a linkage of at least 12 atoms), trimethylolpropane propoxylate tri (meth) acrylate (having sufficient propoxylation units to form a linkage of at least 12 atoms), glycerol ethoxylate tri (meth) acrylate (having sufficient ethoxylation units to form a linkage of at least 12 atoms), glycerol propoxylate tri (meth) acrylate (having sufficient propoxylation units to form a linkage of at least 12 atoms), or mixtures thereof, Ethoxylated pentaerythritol tetra (meth) acrylate (having sufficient ethoxylate units to form a linkage of at least 12 atoms), propoxylated pentaerythritol tetra (meth) acrylate (having sufficient propoxylate units to form a linkage of at least 12 atoms), preferably poly (ethylene glycol) di (meth) acrylate, poly (propylene glycol) di (meth) acrylate, trimethylolpropane ethoxylated tri (meth) acrylate (having sufficient ethoxylation units to form a linkage of at least 12 atoms), or trimethylolpropane propoxylated tri (meth) acrylate (having sufficient propoxylate units to form a linkage of at least 12 atoms).
In some embodiments, acrylates are preferred. In an alternative preferred embodiment, methacrylates are preferred.
In a preferred embodiment, the long crosslinker has a molecular weight of 340Da to 5000Da, preferably 346Da to 3000Da, more preferably 350Da to 1500Da, most preferably 400Da to 1000 Da.
Preferably, the amount of long crosslinker in the monomer mixture is from 0.5 to 25 wt. -%, preferably from 1 to 25 wt. -%, more preferably from 2 to 20 wt. -%, more preferably from 2 to 10 wt. -%, based on the total amount of the monomer mixture.
In some more preferred embodiments, the amount of long crosslinker in the monomer mixture is from 1 to 15 wt.%, preferably from 2 to 12 wt.%. In some more preferred embodiments, the amount of long crosslinker in the monomer mixture is from 1 to 20 wt.%, preferably from 7 to 18 wt.%.
One or more (meth) acrylate monomers of formula (I)
The third essential monomer of the polymeric intraocular lens is one or more (meth) acrylate monomers of formula (I):
wherein:
x is- (C1-C4 alkyl) -O-, - (C1-C4 alkyl) -S-, - (C1-C4 alkyl) -N-or C1-C8 alkyl, wherein C1-C8 alkyl comprises cycloalkyl and one C atom is substituted by a heteroatom selected from O, S and N;
y is absent or-C1-C4 alkyl;
n is 1 to 6;
r is H or CH3。
In formula (I), the alkyl moiety in X and Y may be linear, branched or cyclic, but preferably it is linear. Optionally, the alkyl moiety may be substituted with groups that do not affect the reactivity of the (meth) acrylate moiety, for example, fluoro groups. In a preferred embodiment, X is- (C1-C4 alkyl) -O-or- (C1-C4 alkyl) -S-, more preferably X is- (C1-C4 alkyl) -O-. In a preferred embodiment, n is 1 or 2.
In a preferred embodiment, the (meth) acrylate ester monomer of formula (I) is methoxymethyl (meth) acrylate, methoxyethyl (meth) acrylate, methoxypropyl (meth) acrylate, methoxybutyl (meth) acrylate, ethoxymethyl (meth) acrylate, ethoxyethyl (meth) acrylate, ethoxypropyl (meth) acrylate, ethoxybutyl (meth) acrylate, propoxymethyl (meth) acrylate, propoxyethyl (meth) acrylate, propoxypropyl (meth) acrylate, propoxybutyl (meth) acrylate, butoxymethyl (meth) acrylate, butoxyethyl (meth) acrylate, butoxypropyl (meth) acrylate, or butoxybutyl (meth) acrylate. In some embodiments, acrylates are preferred. In an alternative preferred embodiment, methacrylates are preferred.
In a preferred embodiment, the (meth) acrylate monomer of formula (I) is methoxyethyl methacrylate, methoxypropyl (meth) acrylate, ethoxyethyl (meth) acrylate methyl, methoxyethoxyethyl (meth) acrylate, di (ethylene glycol) ethyl ether (meth) acrylate or triethylene glycol methyl ether (meth) acrylate or ethoxypropyl (meth) acrylate, or propoxyethyl (meth) acrylate.
In a more preferred embodiment, the (meth) acrylate monomer of formula (I) is methoxyethyl acrylate or methoxyethyl methacrylate. Most preferably, the one or more (meth) acrylate monomers of formula (I) include methoxyethyl methacrylate, methoxyethyl acrylate, ethoxyethyl methacrylate, ethoxyethyl acrylate, methoxyethoxyethyl methacrylate, methoxyethoxyethyl acrylate, di (ethylene glycol) ethyl acrylate, and triethylene glycol methyl ether methacrylic acid. In some embodiments, mixtures of methacrylates and acrylates of the same (meth) acrylate monomer of formula (I) are preferred. In some preferred embodiments, a mixture of methoxyethyl acrylate and methoxyethyl methacrylate is preferred.
In a preferred embodiment, the (total) amount of the one or more (meth) acrylate monomers of formula (I) in the monomer mixture is from 15 to 90% by weight, preferably from 18 to 85% by weight.
In some more preferred embodiments, the total amount of (meth) acrylate ester monomer of formula (I) in the monomer mixture is from 35 to 90 wt%, preferably from 42 to 83 wt%, based on the total amount of the monomer mixture. In other more preferred embodiments, the amount of the (meth) acrylate ester monomer of formula (I) in the monomer mixture is from 15 to 55 wt%, preferably from 18 to 45 wt%.
The fourth monomer
The fourth essential monomer in the polymeric intraocular lens composition is one or more C1-C4-alkyl (meth) acrylates, or a combination of phenyl-C1-C4-alkyl (meth) acrylates and cycloalkyl (meth) acrylates. The total amount of alkyl (meth) acrylate or the combination of phenylalkyl (meth) acrylate and cycloalkyl (meth) acrylate is preferably from 5 to 70 wt%, more preferably from 5 to 35 wt%, based on the total monomer mixture.
One or more C1-C4-alkyl (meth) acrylates
One or more C1-C4-alkyl (meth) acrylates may be represented by formula (II):
wherein:
y is-C1-C4 alkyl;
r is H or CH3。
In formula II, the alkyl moiety in Y may be linear, branched or cyclic, but preferably it is linear. Optionally, the alkyl moiety may be substituted with groups that do not affect the reactivity of the (meth) acrylate moiety, for example, fluoro groups.
In a preferred embodiment, the C1-C4-alkyl (meth) acrylate may be methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate [ e.g.n-propyl (meth) acrylate or isopropyl (meth) acrylate ] or butyl (meth) acrylate [ e.g.n-butyl (meth) acrylate, sec-butyl (meth) acrylate, isobutyl (meth) acrylate, tert-butyl (meth) acrylate or cyclobutyl (meth) acrylate ]. Among these (meth) acrylates, methacrylates are preferable. In a particularly preferred embodiment, the C1-C4-alkyl (meth) acrylate is methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, butyl (meth) acrylate or tert-butyl (meth) acrylate, preferably methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate or tert-butyl acrylate, most preferably methyl methacrylate, ethyl methacrylate, propyl methacrylate or butyl methacrylate.
The amount of C1-C4-alkyl (meth) acrylate in the monomer mixture, if present, is preferably from 5 to 75% by weight, more preferably from 15 to 70% by weight, based on the total amount of the monomer mixture.
phenyl-C1-C4-alkyl (meth) acrylates
If present, phenyl-C1-C4-alkyl (meth) acrylates have the formula (III):
wherein:
x is absent or-C1-C4 alkyl;
r is H or CH3。
In formula III, the phenyl moiety may optionally be substituted with groups that do not affect the reactivity of the (meth) acrylate moiety, such as C1-C6 (cyclo) alkyl, C1-C6 (cyclo) alkoxy, or fluoro groups.
In a preferred embodiment, the phenyl-C1-C4-alkyl (meth) acrylate may be phenylmethyl (meth) acrylate (also known as benzyl (meth) acrylate), phenyl (meth) acrylate, 1-phenylethyl (meth) acrylate, 2-phenylethyl (meth) acrylate, 1-phenylpropyl (meth) acrylate, 2-phenylpropyl (meth) acrylate, 3-phenylpropyl (meth) acrylate, phenylcyclopropyl (meth) acrylate, 1-phenylbutyl (meth) acrylate, 2-phenylbutyl (meth) acrylate, 3-phenylbutyl (meth) acrylate, 4-phenylbutyl (meth) acrylate, or phenylcyclobutyl (meth) acrylate.
In a more preferred embodiment, the phenyl-C1-C4-alkyl (meth) acrylates are phenyl (meth) acrylate, phenylmethyl (meth) acrylate, phenylethyl (meth) acrylate.
The amount of phenyl-C1-C4-alkyl (meth) acrylate in the monomer mixture, if present, is preferably from 5 to 40% by weight, more preferably from 8 to 33% by weight, based on the total amount of the monomer mixture.
Cycloalkyl (meth) acrylates
When present, the cycloalkyl (meth) acrylate has the formula (IV):
wherein:
x is absent and is C1-C5 alkyl or- [ (C1-C4 alkyl) -O]n-, where n is 1 to 8;
y is a C3-C18 alkyl group comprising at least one cycloalkyl moiety, wherein the C3-C18 alkyl group optionally comprises one or more heteroatoms selected from O and N groups;
r is H or CH3。
In formula IV, the alkyl moiety in X may be linear, branched or cyclic, but preferably it is linear. Optionally, the alkyl moiety may be substituted with groups that do not interfere with the (meth) acrylate moiety, for example, fluoro groups.
Preferably, X is absent and is methylene, ethylene, propylene, butylene or pentylene, more preferably X is absent and is methylene or ethylene. Most preferably, X is absent.
Y is C3-C18 alkyl comprising at least one cycloalkyl moiety, wherein optionally one or more C atoms of the alkyl group may be substituted by O atoms and/or N atoms, preferably by O atoms. Thus, the total number of C atoms, O atoms and/or N atoms in the group Y does not exceed 18. If present, the O and N atoms are preferably not located in the cycloalkyl moiety.
Preferably, Y comprises a monocyclic ring system, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a bicycloalkyl or tricycloalkyl group comprising any combination of these monocyclic ring systems. Particularly preferably, the bicyclic or tricyclic ring system is norbornyl, isobornyl, or adamantyl.
Y may further comprise a linear or branched alkyl moiety, possibly comprising heteroatoms O and/or N, located between X and the cycloalkyl moiety. Optionally, the cycloalkyl moiety may also be substituted by alkyl, fluoro, hydroxy (OH) or amino (NH)2) And alkyl substituted derivatives (i.e., ether or secondary or tertiary amines) of amino or hydroxy substituted cycloalkyl moieties.
In a preferred embodiment, Y is cycloalkyl, more preferably C3-C10 cycloalkyl.
In a more preferred embodiment, the cycloalkyl (meth) acrylate is cyclopentyl (meth) acrylate, cyclohexyl (meth) acrylate, cycloheptyl (meth) acrylate, norbornyl (meth) acrylate, isobornyl (meth) acrylate, or adamantyl (meth) acrylate. Among these (meth) acrylates, methacrylates are preferable. Alternatively, acrylates are preferred.
The amount of cycloalkyl (meth) acrylate in the monomer mixture is preferably from 10 to 55 wt%, more preferably from 14 to 45 wt%, based on the total amount of the monomer mixture, if present.
Optional monomers in monomer mixtures
As noted above, the polymer composition preferably comprises at least 50% by weight, based on the weight of the composition, of the monomer described above, suitably polymerized. In a preferred embodiment, the polymer composition comprises at least 60 wt.%, preferably at least 70 wt.%, more preferably at least 80 wt.% of the above monomers, suitably polymerized. Thus, to a considerable extent, other conventional monomers than those listed above may be present. These other conventional monomers may be selected from all (meth) acrylic and vinylic monomers common in the field of intraocular lenses that do not fall into one of the above-mentioned basic classes.
In a preferred embodiment, the monomer mixture further comprises a UV light-filtering chromophore (a "UV blocker" or a "UV filter") in an amount suitable to absorb at least 50%, preferably at least 75%, more preferably at least 85% of light irradiation having a wavelength of 350nm to 400nm, preferably benzotriazole-substituted methacrylates. Examples of such UV light filtering chromophores are 2- [3- (2H-benzotriazol-2-yl) -4-hydroxyphenyl ] ethyl methacrylate (CAS 96478-09-0) and 2- (4-benzoyl-3-hydroxyphenoxy) ethyl acrylate (CAS 16432-81-8).
If the composition comprises a UV light filtering chromophore as defined, the amount of the monomer is preferably from 0.1 to 2 wt%, preferably from 0.2 to 1 wt%, more preferably from 0.4 to 0.8 wt% of the monomer mixture.
In other preferred embodiments, the monomer mixture further comprises a blue-filtering chromophore (a "blue filter") in an amount suitable to absorb at least 50%, preferably at least 75%, more preferably at least 85% of light irradiation having a wavelength of 400nm to 500 nm. An example of such a blue light filtering chromophore is a polymerisable yellow dye as described in WO1995/011279a 1. If the composition comprises a defined blue light filtering chromophore, the amount of monomer is preferably from 0.1 to 2 wt%, preferably from 0.2 to 1 wt%, more preferably from 0.4 to 0.8 wt% of the monomer mixture.
Preferred embodiments of the invention
Preferred intraocular lens compositions according to the present invention comprise:
0.1 to 12% by weight, preferably 0.5 to 8% by weight, of short crosslinking agent;
1 to 25% by weight, preferably 2 to 10% by weight, of long crosslinker;
15 to 90% by weight, preferably 18 to 85% by weight, of one or more (meth) acrylate monomers of formula (I);
5 to 75% by weight, preferably 15 to 70% by weight, of one or more C1-C4 alkyl (meth) acrylates of the formula (II) (if present);
5 to 40% by weight, preferably 8 to 33% by weight, of one or more phenyl C1-C4 alkyl (meth) acrylates of the formula (III) (if present);
10 to 55% by weight, preferably 14 to 45% by weight, of cycloalkyl (meth) acrylate of formula (IV) (if present); and
optionally, 0.1 to 2 wt% of a UV light filtering chromophore and/or 0.1 to 2 wt% of a blue light filtering chromophore,
wherein the wt.% is the wt.% in the monomer mixture, based on the total monomer mixture.
In a more preferred embodiment, the intraocular lens composition comprises a polymer mixture of the following monomers:
15 to 90% by weight, preferably 18 to 85% by weight, of one or more (meth) acrylate monomers of formula (I);
5 to 75% by weight, preferably 15 to 70% by weight, of one or more C1-C4 alkyl (meth) acrylates of the formula (II);
1 to 25% by weight, preferably 2 to 10% by weight, of long crosslinker;
0.1 to 12% by weight, preferably 0.5 to 8% by weight, of short crosslinking agent.
This mixture is referred to as embodiment a. In a more preferred embodiment, a UV light filtering chromophore and/or a blue light filtering chromophore as described above is comprised in embodiment a.
In an alternative more preferred embodiment, the intraocular lens composition comprises a polymer mixture of the following monomers:
15 to 90% by weight, preferably 18 to 85% by weight, of one or more (meth) acrylate monomers of formula (I);
5 to 40% by weight, preferably 8 to 33% by weight, of one or more phenyl C1-C4 alkyl (meth) acrylates of the formula (III);
10 to 55% by weight, preferably 14 to 45% by weight, of cycloalkyl (meth) acrylate of the formula (IV);
1 to 25% by weight, preferably 2 to 10% by weight, of long crosslinker;
0.1 to 12% by weight, preferably 0.5 to 8% by weight, of short crosslinking agent.
This mixture is referred to as embodiment B. In a more preferred embodiment, a UV light filtering chromophore and/or a blue light filtering chromophore as described above is comprised in embodiment B.
Other preferred compositions according to the invention comprise polymer mixtures of the monomers of examples 1 to 13. For each of the exemplary compositions in examples 1-13, the listed monomer may be present in an amount that slightly deviates from the amount used in the example. In this context, slight deviations mean that the amount of monomer can be from 5% by weight to 5% by weight lower than the indicated amounts in the examples, preferably from 2% by weight to 2% by weight lower than the exemplary amounts, more preferably from 1% by weight to 1% by weight lower, more preferably from 0.5% by weight to 0.5% by weight higher. Thus, for each lens composition according to the invention in the examples, the listed monomers may be present in the listed amounts ± 5 wt.%, preferably ± 2 wt.%, more preferably ± 1 wt.%, most preferably ± 0.5 wt.%. This slight deviation does not affect the properties of the obtained lens. The present invention thus provides a lens material characterized in accordance with various examples of the present invention.
Properties of the Polymer composition
The intraocular lens compositions defined herein are completely free of vacuoles. This distinguishes the compositions of the present invention from the compositions of the prior art. In the prior art, the tendency of a composition to form vacuoles over time is determined by aging the composition for a particular time at a particular temperature. Common ageing temperatures published in the literature are 37 ℃ or 40 ℃ (for example: in WO2015084788A1, US8449610B2, ageing temperature 45 ℃ for 1 day, then at room temperature for 1-2 hours; in EP1857477B1, a temperature of 33 ℃ is used; in Biomedical optical Express (Biomedical optical Express)4, 8, 2013, 1294-minus 1304, a temperature of 35 ℃ for 8 hours; in J Cataract Refract Surg 2004, 30, 1768-minus 1772, a maximum temperature of 41 ℃ is used; in WO2012106118A2, a temperature of 50 ℃ is used, but the samples are checked step-free at room temperature); for example, the aging time is 1 day or several hours. In prior art experiments on vacuole formation, the aging temperature was never as high as 50 ℃ or higher, followed by cooling at room temperature.
It is known and accepted to age the compositions at higher temperatures to mimic the accelerated aging process under in vivo conditions. Thus, the tendency of the material to form vacuoles after years of use can be simulated by aging at higher temperatures for shorter periods of time. The test involves aging the composition in 0.9% aqueous NaCl at 50 ℃ for 16 hours or more. These conditions are significantly more severe than previously done in the art, and therefore the method is more sensitive in showing vacuole formation after prolonged use in vivo.
Comparison of various known intraocular lens compositions using current standardized and more stringent test conditions has shown that the known compositions are susceptible to vacuolization and/or clouding. However, the compositions of the present invention are completely vacuole free and remain completely vacuole free, and the more severe test conditions of the present invention described above are also used. This makes the present composition particularly suitable for use as a foldable implantable ophthalmic device in ophthalmic surgery, for example in the treatment of cataracts and refractive surgery, for example in the treatment of myopia, since vacuole formation is completely prevented.
The water absorption of the intraocular lens composition defined herein is preferably less than 10% by weight, more preferably less than 5% by weight. The water absorption was measured by weight according to the following procedure: a certain amount of the lens (typically 10 to 20) is allowed to fully hydrate and its weight is measured. Next, the lens was dried in a vacuum oven until the weight stabilized. Subsequently, the water absorption (percentage) is according to the formula (W)Wet-WDry matter)/WDry matterMeasurement was performed at 100%, where WWetIs the weight of the hydrated lens (which of course dries to its surface residual water), WDry matterIs the weight of the lens after complete drying in a vacuum oven.
The intraocular lens compositions defined herein have a viscosity within the limits required for use in intraocular surgery. The tack can be evaluated by the following procedure: a flying saucer-shaped specimen having a diameter of about 14mm, an optical portion of about 6mm, and a plane parallel flap circumference (see fig. 9) thickness of about 0.35mm was folded in half, and pressure was applied with a finger for 1 or 2 seconds or more to bring one half of the flap of the specimen into contact with the other half of the same specimen and to press it. Subsequently, the pressure is released. The non-adhesive sample will easily return to its original shape, while the adhesive sample will remain folded because the interaction between the lens halves is too strong to allow the lens to unfold. Furthermore, and most importantly, when finished lenses of current formulations were injection tested using an injector with a 2.2mm nozzle and viscoelastic media, no unfolding due to stickiness was ever observed.
The intraocular lens compositions defined herein are sufficiently soft to be foldable. The development time is 1 to 150 seconds, preferably 3 to 120 seconds, more preferably 5 to 30 seconds. The deployment time was determined by recording a video of the lens after it passed through the injector nozzle and was deposited in a small water bath at 26 ℃ (simulating surgical conditions) to accurately observe and time the deployment process.
Accordingly, the present invention also provides an intraocular lens, an artificial cornea, a corneal ring, a corneal implant (corneal implant) or a corneal inlay (corneal inlay) comprising an intraocular lens composition as defined herein.
Method for preparing intraocular lens composition
The present intraocular lens compositions may be prepared by generally known polymerization processes using the monomer mixtures defined above as the starting mixture for the polymerization. In a preferred embodiment, the polymerization process is a free radical polymerization process. In other preferred embodiments, the polymerization is carried out in one step using the monomer mixture as a reactant. The monomer mixture may suitably comprise a solvent, as is known in the art. However, the polymerization mixture preferably consists only of the monomers to be polymerized and of the polymerization initiator.
Accordingly, the present invention also relates to a method of making an intraocular lens composition as described herein, the method comprising the steps of:
1) preparing a monomer mixture as described above;
2) preferably, a free radical polymerization initiator is added;
3) allowing polymerization to occur;
4) extraction is carried out using a suitable solvent, if necessary, to eliminate residual unreacted monomer or other impurities.
Suitable polymerization initiators are free-radical polymerization initiators. The compounds are well known and any compound known for this purpose may be used. Preferably, the initiator is a diazo initiator, such as 2, 2-azobis (2, 4-dimethylvaleronitrile), 2' -azobis (2-methylpropionitrile), azobisisobutyronitrile lauroyl peroxide, benzoyl peroxide, but photoinitiators, such as phenylbis (2,4, 6-trimethylbenzoyl) phosphine oxide, may also be used. Further preferably, the initiator is an organic peroxide, such as di-tert-butyl peroxide, benzoyl peroxide, lauroyl peroxide or methyl ethyl ketone peroxide.
The amount of initiator depends on the type of initiator and the specific monomer mixture, as known to the skilled person. Generally, the amount of initiator expressed as a weight% of the monomer mixture may be from 0.1 to 2 weight%, preferably from 0.2 to 1.5 weight%, more preferably from 0.5 to 1 weight%.
In certain embodiments, it is desirable to reduce the atmospheric oxygen content prior to polymerization, but in other embodiments of the present compositions, polymerization may be carried out in an oxygen-containing atmosphere (e.g., air). This is an advantage because it can avoid the use of an inert atmosphere as is conventional. The polymerization of the present composition may be carried out, for example, in a gas atmosphere of about 21% oxygen. Preferably, the polymerization is carried out in an atmosphere having an oxygen content of preferably less than 5% and most preferably less than 1%.
Alternatively, the polymerization may be carried out in an inert atmosphere, as is known in the art. The inert atmosphere may comprise nitrogen or argon (or mixtures thereof) or other known inert gases.
Polymerization is typically carried out in a mold formed of polypropylene or other suitable material that provides the lens shape and optical properties, or is fabricated in the form of a sheet or button of sufficient thickness to shape the lens by classical lathing cutting techniques (lath cut technology) known in the art.
Suitably, after polymerization is complete, the resulting polymer composition is removed from the mold and may optionally be cut to form a haptic feedback portion (haptic portion) of the lens. Upon completion, the lens is suitably stored in a water-based system in a dry or hydrated form.
For purposes of clarity and brevity, features are described herein as part of the same or separate embodiments. It is to be understood, however, that the scope of the present invention may include embodiments having combinations of all or some of the features described. The invention will now be illustrated by the following non-limiting examples.
According to embodiments of the present invention
Examples 1 to 13 show the composition of the compositions according to the invention.
Example 1:
example 2:
example 3:
example 4:
example 5:
example 6:
example 7:
example 8:
example 9:
example 10:
example 11:
example 12:
example 13:
the components were mixed together and stirred at room temperature until homogeneity was achieved. The mixture is then filtered through a 0.45 μm inert filter and used to fill a mold made of polypropylene or other suitable material.
Next, the filled mold was placed in an oven and the polymer mixture was cured by raising the temperature from room temperature (about 20 ℃) to 90 ℃ over a period of 5 hours, and then maintaining the temperature at 90 ℃ for another 6 hours. As will be appreciated by those skilled in the art, the thermal profile can be modified according to the particular mixture to tune the results.
At this point, the mold was allowed to cool to room temperature, then opened and the piece recovered. Depending on the type of die, further processing may be performed, such as turning (lathing) and milling (milling) as is known in the art. It is possible to consider the extraction of residual unreacted monomers.
Comparative example
Examples 14-17 show compositions outside the scope of the present invention that do suffer from vacuole formation or other problems.
Example 14:
example 15:
example 16:
example 17:
example 18:
lenses (lens) were prepared from these compositions according to the same procedure as described above for examples 1-13.
The present invention improves upon known lens materials and provides intraocular lens compositions that are completely free of vacuoles, have appropriately adjusted hardness to provide comfortable deployment speeds, ease of folding, and comfortable injection forces, and do not exhibit prohibitive tackiness, even under harsh test conditions. Furthermore, the Refractive Index (RI) is in all cases within acceptable values and the optical quality (MTF) is always very good.
Flash test
The flash part test was performed as follows: the lenses were placed in 7ml vials filled with 0.9% NaCl aqueous solution, the vials were held at 50 ℃ for 16 hours or more, cooled at room temperature (about 20 ℃) for 0.5 to 1 hour, the lenses were removed from the vials, and analyzed under a microscope (Olympus BX50) under dark field illumination at a magnification of 20 to 100, if necessary up to 500. On a microscope, retro-illumination (retroillumination) was used and no filters were added. The formation of vacuoles was visually assessed.
The results are shown in fig. 1-13 for the lenses of examples 1-13. As can be seen, no vacuoles were observed in the lenses made according to the invention. The flash test results, as well as other parameters, are summarized in table 1.
The lenses of examples 14-18 were outside the scope of the present invention. The lenses of examples 14-17 did exhibit vacuoles; the lens of example 18 whitens after hydration in water and exhibits some vacuoles already before the flash test is performed. These results are summarized in table 2.
For comparison, the following commercially available lenses were used for the flash test:
·AcrySof(R)(Alcon)
·iSert(R)255(HOYA Surgical Optics)
·AvanseeTM(Kowa pharmaceutical Europe)
·Tecnis(R)(Johnson&Johnson Surgical Vision)
·AsqelioTM(AST Products)
the results are shown in FIGS. 14-18 and summarized in Table 3.
In the case of the Alcon AcrySof (fig. 14), Hoya 255 (fig. 15) and Tecnis (fig. 17) lenses, many vacuoles were seen. The hazy appearance of the Avansee lens (fig. 16) after the glitter test can be attributed to the formation of countless very small vacuoles. In the 100 x photograph, residual droplets are seen which are not forcibly removed so as not to affect the sparkle inside the material.
In the case of the Asqelio lens (fig. 18), vacuoles were also visible. In the 100 x photograph, residual droplets are seen which are not forcibly removed so as not to affect the sparkle inside the material.
Table 1: results of the flash part test on examples 1 to 13
The unfolding speed is as follows: measurements were made after injection into a 26 ℃ water bath (using a 2.2mm diameter syringe tip; all lenses were injected with an ophthalmic viscoelastic solution). Viscosity: according to the observation, folding a flying saucer-shaped sample into two halves; however, none of the lenses in the test could be unfolded after injection, so the viscosity could be considered very low in all cases. RI: measurements were made at room temperature using a refractometer (IndexInstrument Limited, model CRL 12-70) at a wavelength of 589nm (except for example 13, all samples were hydrated in demineralized water, example 13 was hydrated in a 0.9% aqueous NaCl solution). MTF was measured by Lamda-X on PMTF (except for example 13, all samples were hydrated in demineralized water, example 13 was hydrated in 0.9% NaCl aqueous solution).
Table 2: results of testing for flashing portion on comparative examples 14 to 18
Example numbering
Flashing part
14
Some vacuoles
15
Many vacuoles
16
Many vacuoles
17
Some vacuoles and very blurry
18
(which whitens after hydration)
Table 3: flash test results on selected commercially available lenses
Other comparative examples
Example 19
Composition of
Parts by weight
By weight%
Acrylic acid 2-phenoxy ethyl ester
40
31.0
2-hydroxyethyl methacrylate
25
19.4
Acrylic acid ethyl ester
60
46.5
Ethylene glycol dimethacrylate
4
3.1
Example 20
Composition of
Parts by weight
By weight%
Acrylic acid 2-phenoxy ethyl ester
60
50.4
2-hydroxyethyl methacrylate
15
12.6
Acrylic acid ethyl ester
40
33.6
Ethylene glycol dimethacrylate
4
3.4
Examples 19 and 20 show comparison with the product of us 6140438. Examples 4 and 6 in US 6140438 were reproduced as shown in said document. Polymerizable components identified in tables 19 and 20 and 1 part by weight of 2,2' -azobis (2, 4-dimethylvaleronitrile) as a polymerization initiator per 100 parts by weight of the total amount of the polymerizable components were mixed, and the mixture was poured into a casting mold having a desired intraocular lens shape. The casting mold was put into an oven and subjected to thermal polymerization molding at 50 ℃ for 24 hours. The casting molds were then transferred to an air-circulating dryer, heated at a rate of 10 ℃/hour from 65 ℃ to 130 ℃, and then cooled to room temperature. Then, the irradiation of the LED black light for more than one hour is performed by the irradiation equipment. Thereafter, the obtained polymer was taken out from the casting mold and further dried in an oven at 50 ℃ for 2 days.
The same prepared lens composition was subjected to the curing procedure described in examples 1-13 instead of the curing procedure described in US 6140438. The results were the same for both curing procedures.
The flash part test was performed using the harsh method described in examples 1-13. The results for the lenses of examples 19 and 20 are shown in fig. 20-21 and summarized in table 4.
Table 4: results of testing for flashing portion on comparative examples 19 to 20
Example numbering
Flashing part
19
Some vacuole and blur
20
Many vacuoles and very blurry
As shown in table 4, lens materials prepared from the intraocular lens compositions according to US 6140438 contain vacuoles and appear hazy when viewed under an LED lamp (hazy). Thus, even under the soft conditions and short time frame employed in US 6140438, the lens of US 6140438 is said to be vacuole free, and the harsher conditions that simulate the accelerated aging process under in vivo conditions indicate that the lens of US 6140438 is not, in fact, vacuole free and can become hazy. It follows that the performance of the lens material according to US 6140438 is significantly worse than the lens material according to the invention which exhibits no vacuoles and does not become smeared.