WO2002077044A2

WO2002077044A2 - Polymer composition for intraocular lens

Info

Publication number: WO2002077044A2
Application number: PCT/GB2002/001460
Authority: WO
Inventors: Caroline Magnin-Robert; Richard Young; Jan West; John Mcgregor
Original assignee: Contamac Ltd
Priority date: 2001-03-26
Filing date: 2002-03-25
Publication date: 2002-10-03
Also published as: EP1381636A2; GB2375114A; WO2002077044A3; GB0207013D0; AU2002242865A1; GB0107540D0

Abstract

A polymerisable composition comprises one or more monomers having the formula: (A) wherein: -X is -H or -CH3; -Y is -H or a C1 to C10 alkyl group; -Z- is -C(=0)- or is a covalent bond; -Ar is a phenyl group which is unsubstituted or substituted with one or more of -CH3, -C2H5, -(n-C3H7), -(iso-C3H7), -OCH3, cyclohexyl, -F, -Cl, -Br, -I, phenyl, and benzyl; and m is an integer having a value of from 1 to 10, with the proviso that if m is 1 then Z is -C(=O)-.

Description

POLYMER COMPOSITION TECHNICAL FIELD

The present invention relates ^"to a polymerisable composition, a polymer formed from the polymerisable composition, and ophthalmic lenses and ophthalmic lens blanks formed from the polymer.

BACKGROUND ART

Contact and intraocular ophthalmic lenses are devices for correcting defective vision. In particular, it has become commonplace to replace cataractous lenses with intraocular lenses (IOLs) using surgical procedures.

A typical procedure involves fragmenting the patient's cataractous lens by ultrasonic vibration, aspirating the fragmented lens pieces from the patient's eye through an incision in the eye, and then inserting an IOL into the eye through the same incision.

In order to reduce surgical trauma, it is advantageous to minimise the size of the incision. For this reason, foldable IOLs have been developed which can be shaped into a small package for insertion through the incision and which unfold into a final shape after being located in the eye. A significant class of foldable IOLs are formed from flexible polymers which are capable of unfolding at the temperature of the eye (i.e., about 37 °C) into an appropriate lens shape.

Hydrophobic acrylic-based polymers have been used for forming flexible IOLs of this type, e.g., as disclosed by US-5674960, US-5922821 and WO 96/40303. Such polymers are rollable and foldable, and have relatively high refractive indices (which enables IOLs to be made thinner without sacrificing optical refractory power) . Conventionally, IOLs formed of these polymers are produced in a one-step moulding process which gives the IOL its final lens shape. The glass transition temperatures, T_g, for the polymers are generally lower than 20°C so that the IOLs can be folded at room temperature.

DISCLOSURE OF INVENTION

The present invention is at least partly based on the recognition that conventional hydrophobic acrylic-based polymers are not particularly suited to alternative processes, such as machining, for providing the final lens shape. An object of the present invention is to improve the machinability of polymers for use in flexible IOLs.

A first aspect of the present invention provides a polymerisable composition comprising one or more monomers having the formula:

wherein:

-X is -H or -CH₃;

-Y is -H or a Ci to Cio alkyl group, and is preferably -H or -CH₃;

-Z- is -C(=0)- or is a covalent bond;

-Ar is a C5 to C20 aryl group and preferably a phenyl group which is unsubstituted or substituted with one or more of -CH₃, -C₂H₅, -(n-C₃H₇), -(iso-C₃H₇) , -OCH₃, cyclohexyl, -F, -Cl, -Br, -I, phenyl, and benzyl; and, m is an integer having a value of from 1 to 10, preferably 2 to 10, more preferably from 4 to 8, and desirably 6, with the proviso that if m is 1 then Z is -C(=0)-.

The term "alkyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 10 carbon atoms, which may be aliphatic or alicyclic, or a combination thereof, and which may be saturated, partially unsaturated, or fully unsaturated.

The term "aryl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound.

The term "aromatic, " as used herein, pertains to compounds and/or groups which have one ring, or two or more rings (e.g., fused), wherein at least one of said ring(s) is aromatic.

We have found that polymer IOLs formed from such a composition can be sufficiently flexible to fold or roll the IOLs to a small size for surgical insertion.

However, notwithstanding this flexibility, the physical properties of the polymers can be such that the polymers are machinable at temperatures of 20 °C or higher, and/or at high speeds (which is desirable from the point of using conventional ophthalmic lens machine tooling, e.g., of the type used to machine contact lenses) . Machining with such tooling would be difficult to perform on conventional low T_g polymers . We believe that the -CH₂-CHY-0- group or groups of the monomer side chain play a significant part in providing the advantageous physical properties of the polymers.

The amount of the above monomers in the composition may be at least 20% by weight of the composition, preferably at least 50% and more preferably at least 70%.

The composition may further comprise one or more second monomers for forming a copolymer with the first monomer, the second monomers having an acrylate or methacrylate group. For example, the second monomers may be methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, hexyl acrylate, cyclohexyl acrylate, methoxymethyl acrylate, ethoxyethyl acrylate, methoxyethyl acrylate, ethoxymethyl acrylate, phenylether acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, hexyl methacrylate, cyclohexyl methacrylate, methoxymethyl methacrylate, ethoxyethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, and phenylether methacrylate. Preferably, the amount of the second monomers in the composition is at least 5% by weight of the composition, more preferably at least 20% and desirably at least 30%.

The composition may further comprise one or more hydrophilic third monomers for forming a copolymer with the first monomer and optionally the second monomer. For example, the third monomers may be 2~hydroxyethyl methacrylate, hydroxypropyl methacrylate, N-vinyl pyrolidone, methacrylic acid, acrylic acid, acrylamide, methacrylamide, N,N-dimethyl acrylamide, hydroxyethyl acrylate and hydroxypropyl acrylate. Preferably, the amount of the third monomers in the composition is less than 50% by weight of the composition, more preferably less than 25% by weight and desirably less than 15% by weight. The composition may further comprise one or more crosslinking fourth monomers having a plurality of ethylenically unsaturated groups. For example, the fourth monomers may be ethylene glycol dimethylacrylate, diethylene glycol dimethylacrylate, allyl methacrylate, 1, 3-propanediol dimethacrylate, di-allyl maleate, 1, 6-hexanediol dimethacrylate, 1, 4-butanediol dimethacrylate and 1, 4-butanediol diacrylate. Preferably, the amount of the fourth monomers in the composition is at least 0.1% by weight of the composition, more preferably at least 0.5% and desirably at least 1% or 4%.

The optional addition of the second, third and/or fourth monomers to the composition can be useful for adjusting the physical or optical properties of the polymer formed from the composition. The composition may further comprise conventional compounds, including but not limited to a thermally- or light-activated polymerisation initiator (preferably in an amount of up to 5% by weight of the composition) , a UV-light absorber (preferably in an amount of up to 5% by weight of the composition) , or a blue-light absorber (preferably in an amount of up to 0.5% by weight of the composition), or a combination thereof.

Another aspect of the present invention provides a polymer formed from the polymerisable composition of the previous aspect.

In one embodiment the polymer has a T_g (as measured by dynamic mechanical thermal analysis, DMTA) in the range of 0 to 50 °C, preferably 0 to 35°C (more preferably in the range 5 to 30°C) or 10 to 40°C.

Preferably the polymer has an elongation at 20°C of at least 50% (e.g., from 50% to 250%), and more preferably of at least 75% (e.g., from 75% to 150%).

The polymer may have a refractive index (e.g., as measured by an Abbe refractometer) at 20 °C of at least 1.49.

Further aspects of the present invention provide a blank for an ophthalmic lens formed from the polymer of the previous aspect, and an ophthalmic lens (which is preferably an IOL) formed from the polymer of the previous aspect. Another aspect of the present invention provides a method of forming an ophthalmic lens comprising the steps of:

(a) providing a blank according to a previous aspect of the invention; and

(b) machining the blank to form an ophthalmic lens. Thus a finished IOL can be machined using milling and lathe cutting processes familiar to those skilled in the art. This has the advantage that a mould is not required to form a finished IOL, such moulds being relatively expensive articles and each mould in any event being capable of producing an IOL of only one geometry (and hence one focussing power) . Of course, this is not to exclude that the finished lens shape be formed by moulding (i.e., without a machining step) if desired.

As discussed above, the physical properties of the polymer, which we believe are due in large part to the first monomer but may be modified by the second, third and fourth monomers, facilitate the machining of the ophthalmic lens according to this aspect of the invention.

DETAILED DESCRIPTION

The present invention will now be described with reference to specific embodiments.

The monomer poly (propylene glycol) 6 monobenzoate monomethacrylate (code named DP237) is formable by the following method.

It is extremely important to ensure that all apparatus is thoroughly dried before use and is free of moisture. 1, 2-propanediol is placed in a round-bottomed flask set up for reflux with the exclusion of atmospheric moisture. Potassium metal is slowly added to the mixture with the temperature of the mixture being controlled by placing the round-bottomed flask in a water/ice bath, if required. When the metal has been added and the alkoxide has been produced, the anionic polymerisation is then carried out by the addition of propylene oxide. By selection of the ratio of the amount of alkoxide to the amount of propylene oxide, the desired average chain length can be achieved. However, it must be ensured that water is not present at any stage during the reaction. The reaction is conveniently carried out in tetrahydrofuran (THF) . When all the reactants have been consumed, the alkoxide functionalities are removed by the addition of a solvent capable of abstracting a proton. Methacrylic acid is converted to its acid chloride by the addition of thionyl chloride using standard reflux conditions. Any excess thionyl chloride is easily removed by distillation. The acid chloride is then reacted with the product of the first reaction. Since the alcohol is losing a proton, the primary alcohol is much more reactive than the secondary alcohol site and, as such, the product is a hydroxy terminated methacrylate. At this point, the product is isolated and any impurities, such as hydroxypropyl methacrylate, are removed.

Finally, the aromatic portion of the molecule is added by the Schotten-Baumann technique. The benzoyl acid is converted to its acid chloride, again by reaction with thionyl chloride followed by purification by distillation. The acid chloride is then added in portions to the hydroxy compound, this time in dichloromethane, in the presence of pyridine . After each addition, the mixture is shaken vigorously, since the aromatic acid chlorides are not as reactive as the aliphatic derivatives. The pyridine is present to neutralise the hydrogen chloride that would otherwise be liberated. The resulting product is washed with water, since the dichloromethane is immiscible with water, and the pH is noted. Any acid that is present is removed by treatment with aqueous ammonia solution. Other derivatives can be produced using different acid chloride derivatives in the final reaction.

Three polymers based on this monomer were formed from respective polymerisable compositions according to the following table:

where MMA is methyl methacrylate, HEMA is 2-hydroxyethyl methacrylate, DAM is di-allyl maleate (a crosslinking agent) , and AIBN is azo iso butyronitrile (a thermally-activated polymerisation initiator) .

Each composition was thoroughly mixed and poured into a circularly cylindrical mould which was then evacuated and sealed. The compositions were polymerised at 60°C for 18 hours to form cylindrical blanks which were then removed from the moulds.

Each blank had a diameter of 12.5 mm and a length of 7 mm. For each blank the values of the refractive index at 20°C, the Shore D hardness at 20°C and the T_g was measured (the refractive index were measured by an Abbe refractometer, and the T_g by dynamic mechanical thermal analysis) . The measured values are given in the table above.

Using conventional milling and lathe cutting processes, each blank was machined to a bi-convex shape (diameter 6 mm, central thickness 0.75 mm) corresponding to the central optic portion of a finished IOL.

These IOL central optic portions were rolled at 35°C, and inserted into narrow tubes of approximately 3 mm internal diameter. The rolled up lenses and tubes were then placed in an environmental cabinet at 35°C for a period of time to simulate the conditions in a human eye. When the lenses and tubes had had sufficient time to reach equilibrium with these conditions, the lenses were removed from the tubes. In each case the IOL portion spontaneously unrolled and assumed its original bi-convex shape in less than one minute. This demonstrates that the IOL portions were not damaged by rolling and storage, and suggests that they are suitable for use in cataractous lens replacement surgery.

Claims

1. A polymerisable composition comprising one or more monomers having the formula :

wherein :

-X is -H or -CH₃;

-Y is -H or a Ci to Cio alkyl group; -Z- is -C (=0) - or is a covalent bond; -Ar is a phenyl group which is unsubstituted or substituted with one or more of -CH₃, -C₂H₅, -(n-C₃H₇), - (iso-C3H₇) , -OCH₃, cyclohexyl, -F, -Cl, -Br, -I, phenyl, and benzyl; and m is an integer having a value of from 1 to 10, with the proviso that if m is 1 then Z is -C(=0)-.

2. A polymerisable composition according to claim 1, wherein the amount of the monomers in the composition is at least 20% by weight of the composition.

3. A polymerisable composition according to claim 1 or 2, which further comprises one or more second monomers for forming a copolymer with the first monomer, the second monomers having an acrylate or methacrylate group.

4. A polymerisable composition according to claim 3, wherein the second monomers are selected from methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, hexyl acrylate, cyclohexyl acrylate, methoxymethyl acrylate, ethoxyethyl acrylate, methoxyethyl acrylate, ethoxymethyl acrylate, phenylether acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, hexyl methacrylate, cyclohexyl methacrylate, methoxymethyl methacrylate, ethoxyethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, and phenylether methacrylate.

5. A polymerisable composition according to claim 3 or 4, wherein the amount of the second monomers in the composition is at least 5% by weight of the composition.

6. A polymerisable composition according to any one of claims 1 to 5, further comprising one or more hydrophilic third monomers for forming a copolymer with the first monomer .

7. A polymerisable composition according to claim 6, wherein the third monomers are selected from 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate, N-vinyl pyrolidone, methacrylic acid, acrylic acid, acrylamide, methacrylamide, N,N-dimethyl acrylamide, hydroxyethyl acrylate and hydroxypropyl acrylate.

8. A polymerisable composition according to claim 6 or 7, wherein the amount of the third monomer in the composition is less than 50% by weight of the composition.

9. A polymerisable composition according to any one of claims 1 to 8, further comprising one or more crosslinking fourth monomers having a plurality of ethylenically unsaturated groups.

10. A polymerisable composition according to claim 9, wherein the fourth monomers are selected from ethylene glycol dimethylacrylate, diethylene glycol dimethylacrylate, allyl methacrylate, 1, 3-propanediol dimethacrylate, di-allyl maleate, 1, 6-hexanediol dimethacrylate, 1, 4-butanediol dimethacrylate, and 1, 4-butanediol diacrylate.

11. A polymerisable composition according to claim 9 or 10, wherein the amount of the fourth monomers in the composition is at least 0.1% by weight of the composition.

12. A polymerisable composition according to any one of claims 1 to 11, further comprising a thermally- or light- activated polymerisation initiator, a UV-light absorber, or a blue-light absorber, or a combination thereof.

13. A polymer formed from the polymerisable composition of any one of claims 1 to 12.

14. A polymer according to claim 13, having a glass transition temperature in the range 0 to 50°C.

15. A polymer according to claim 13 or 14, having an elongation at 20°C of at least 50%.

16. A polymer according to any one of claims 13 to 15, having a refractive index at 20°C of at least 1.49.

17. A blank for an ophthalmic lens formed from the polymer of any one of claims 13 to 16.

18. An ophthalmic lens formed from the polymer of any one of claims 13 to 16.

19. An ophthalmic lens according to claim 18 which is an intraocular lens.

20. A method of forming an ophthalmic lens comprising the steps of:

(a) providing a blank according to claim 17; and

(b) machining the blank to form an ophthalmic lens.