WO1998026813A1

WO1998026813A1 - Flexible intraocular lens made of hydrophilic acrylic material

Info

Publication number: WO1998026813A1
Application number: PCT/FR1997/002310
Authority: WO
Inventors: Franck Villain; Laure-Anne Leguay; Angel Ortuno
Original assignee: Corneal Industrie
Priority date: 1996-12-17
Filing date: 1997-12-16
Publication date: 1998-06-25
Also published as: JP2001506884A; FR2757065A1; EP0946219A1; CA2275325A1; FR2757065B1

Abstract

The invention concerns novel flexible intraocular lenses made of an hydrophilic acrylic material and the method for preparing them. Said hydrophilic acrylic material which constitutes their optic part, or even their optic and haptic parts, is a cross-linked copolymer of hydroxyethyl methacrylate (HEMA) and of ethyl methacrylate (EMA).

Description

Soft intraocular lens made of hydrophilic acrylic material

The present invention relates to new flexible intraocular lenses made of a hydrophilic acrylic material and to a process for their preparation. These soft, hydrogel intraocular lenses are foldable and can be inserted through small incisions (3 to 4 mm).

The most widely used material to date for the manufacture of intraocular lenses or IOLs is polymethyl methacrylate (polyMMA). The first IOLs in this material were made in the early 1950s. Harold Ridley chose this material because he found, during the Second World War, that pieces of polyMMA cockpit, found in the eyes of airplane pilots, after accident, were very well tolerated, causing neither inflammation nor reaction. This material (polyMMA) has satisfactorily shown its excellent biocompatibility, in more than forty years of use. It continues, as indicated above, to constitute the most used material in this application. However, its lack of flexibility is a major drawback. Lenses made of this material do not adapt to new less invasive surgical techniques than those of previous years, such as phacoemulsification. The trend is in fact to reduce the size of the incision necessary to extract the lens, in order to reduce, as much as possible, post-operative consequences such as astigmatism. Currently, the size of the incisions made is approximately 3 mm. It also seems that the lens cannot have a dimension smaller than the maximum aperture diameter of the pupil: this value is approximately 4.5 mm; hence the need to now fold the lenses for their introduction through small incisions ... The folding of polyMMA lenses being excluded, we tried, to keep the advantages of said polyMMA, to make lenses of said material, oval shape ... However, such lenses did not give the expected results: surgeons reported a greater frequency of visual disturbances among patients who received an oval IOL. Such disturbances have been attributed to the existence of a critical IOL diameter, below which the retina also receives the light diffracted by the edges of the lens (the diffraction of light on the lens is caused by the fact that the diameter of the pupil may be larger than the diameter of the lens). Since it has been established that the optics of an intraocular lens cannot have a diameter of less than 5 mm (value including a certain safety margin), it is therefore necessary to bend said lens for its introduction into the capsule (through incisions of a size less than 5 mm), and it is therefore imperative to make said lens in a flexible material.

For the manufacture of flexible lenses, two main families of materials are used to date: silicones or more precisely polysiloxanes and acrylic polymers. Among said acrylic polymers, a distinction is made between hydrophilic - hydrogels - and non-hydrophilic. Said hydrophilic acrylic polymers seem to have the advantage of limiting cell adhesion and therefore cell proliferation. Those skilled in the art are aware that the major complication encountered in cataract surgery is the uncontrolled proliferation of epithelial cells, which ultimately results in secondary cataracts ...

The ALCON company launched in 1984, under the trade name Iogel®, a first generation of intraocular lenses made of poly (hydroxyethyl methacrylate) (polyHEMA). Mechanical problems have been encountered with this material ... The Iogel® implant has been abandoned.

Currently, on the market, two companies market intraocular lenses, all or part of which is made of a hydrophilic acrylic material: the company STORZ and the company MENTOR.

The company STORZ markets such lenses, as described in application EP-A-0 492 126, under the name Hydroview®. The material constituting the optics of said lenses is a copolymer of hydroxyethyl methacrylate (HEMA) and hydroxyhexyl methacrylate (HHMA). Said copolymer is obtained from two hydrophilic monomers: one very hydrophilic (HEMA) and the other much less hydrophilic (HHMA). The equilibrium water content of said copolymer is 18%.

The company MENTOR markets such lenses, in particular described by William J. Fishkind, MD, in Chapter 11 (p 197-21 1) of the book "Foldable intraocular lenses", edited by RG Martin, JP Gilles and DR Sanders in Slack editions , Thorofare 1993, under the trade name Memorylens®. The intervening copolymer is a copolymer of hydroxyethyl methacylate (HEMA) and methyl methacrylate (MMA). In this case, the hydrophilicity of hydroxyethyl methacrylate (HEMA) is lowered by the intervention of a hydrophobic monomer (MMA). The water content, at equilibrium, of said copolymer (poly (HEMA / MMA): hydrophilic / hydrophobic) is 20%. Said lenses, in said copolymer: poly (HEMA / MMA) cannot (unlike previous Hydroview®) be folded at room temperature. The implant must be warmed up beforehand.

In this context, the Applicant has developed, for its part, intraocular lenses, all or part of which is made of a hydrophilic acrylic material. It in fact proposes to produce such lenses from an original material which gives them very interesting, "optimized" mechanical and optical properties. Said material has been developed, in the context of the present invention, taking especially into account the following five parameters:

- resistance to breakage: the lenses of the invention must not be damaged during pre-operative and intra-operative manipulations;

- elongation at break;

- "elasticity", measured by a module of Young's modulus type (average modulus): the lenses of the invention must bend easily while having sufficient rigidity for their good behavior in the eye; - the refractive index: a high value of this index limits the thickness of the lens;

- the expansion coefficient, during hydration: a low coefficient allows better control of the lens manufacturing process;

- equilibrium water content. The intraocular lenses of the invention have, conventionally, an optic and a haptic. Said optic - or even said optic and said haptic - is made of a flexible hydrophilic acrylic material. In this, said intraocular lenses or implants of the invention - whether they are monobloc or composite - are flexible, foldable lenses, of the type of those of the prior art presented above.

Typically, said “optimized” hydrophilic acrylic material (which constitutes at least their optics, even their optics and their haptics) is a crosslinked copolymer: of hydroxyethyl methacrylate (HEMA) and ethyl methacrylate (EMA).

Said hydroxyethyl methacrylate (HEMA) gives the lenses of the invention their hydrophilicity, their flexibility while said ethyl methacrylate (EMA) is used to optimize their mechanical properties. The intervention of said EMA proves to be much more advantageous, according to the invention than that, according to the prior art, of MMA. Quantitatively, said intervention must obviously remain within reasonable limits so as not to compromise the hydrophilic nature of the final copolymer. We see below that said final copolymer is generally obtained by copolymerization, per 100 parts by weight of monomers: HEMA + EMA, from 77.5 to 87.5 parts by weight (advantageously, from 80 to 85 parts by weight) of HEMA and from 12.5 to 22.5 parts by weight (advantageously from 15 to 20 parts by weight) of EMA. According to a particularly advantageous variant, it is obtained by copolymerization of 82.5 parts by weight of HEMA and 17.5 parts by weight of EMA.

Thus, the acrylic copolymer which constitutes at least the optics of the intraocular lenses of the invention re rnufecrλm / TeA he fHEMAl units and [EMA] units in a ratio R: R = ^. -, generally between 3.0 and 6.1, advantageously between 3.5 and 5 and being, according to a preferred variant, 4.1.

Said poly [HEMA / EMA] copolymer is, as specified above, crosslinked. Such crosslinking is essential to ensure the cohesion of the material and its stability. A cross-linking agent - bifunctional - must therefore intervene, in an effective amount, during the copolymerization of the HEMA and EMA monomers. This effective amount - generally, at most a few parts by weight: in principle between 0.5 and 5 parts by weight, advantageously between 0.5 and 2.5 parts by weight, per 100 parts by weight of monomers: HEMA + EMA - must obviously remain reasonable. It is not a question of the intervening crosslinking agent constituting a comonomer and consequently modifying the properties, in particular mechanical, of the poly (HEMA / EMA) copolymer.

In any event, those skilled in the art are aware that the increase in the level of crosslinking agent involved decreases the water content of the hydrogels and increases their glass transition temperature.

It is indicated here that said crosslinking agent intervenes in the structure of the copolymer, generally in an amount such that the ratio:

total number of reactive functions of said crosslinking agent present total number of reactive functions (methacrylates) of the reactants present (HEMA, EMA)

is between 6.10 ^~ 3 and 60.10 ^~ 3. Said ratio R 'is advantageously 10 "2.

As regards the reactive functions of said crosslinking agent, they are advantageously acrylate and / or methacrylate functions. A person skilled in the art knows many crosslinking agents which carry such functions, and in particular: butanediol dimethacrylate and diacrylate, hexanediol dimethacrylate and diacrylate, decanediol dimethacrylate and diacrylate, ethylene glycol dimethacrylate (EDMA), tetraethylene glycol dimethacrylate. In the context of the present invention, the intervention of the crosslinking agents listed above, and in particular that of EDMA, is recommended in a nonlimiting manner.

Thus, the poly (HEMA / EMA) copolymer, constituting the optics, even optics and haptics, of the intraocular lenses of the invention is it crosslinked by crosslinking agents of this type (or d 'an equivalent type) of which we obviously find traces in its skeleton.

We can generally find traces of another monomer chemically linked to said skeleton. In fact, those skilled in the art are aware of the advantage of stabilizing a UV filter in the structure of intraocular lenses. Thus, according to an advantageous variant, the crosslinked poly (HEMA / EMA) copolymer constituting the optics, or even optics and haptics, of the intraocular lenses of the invention, does it contain an effective amount of '' a UV filter chemically linked to its skeleton (stably). For the formation of such a chemical bond, the intervening compound (which has a chromophore) must obviously have an adequate reactive chemical function of the double bond type, acrylate or methacrylate function ...

A person skilled in the art knows such compounds and several of them are commercially available, in particular: 4- (2-acryloxyethoxy) -2-hydroxy benzophenone, 4-methacryloxy-2-hydroxy benzophenone (MOBP), 1 , 3-bis- (4-benzoyl-3-hydroxyphenoxy) -2-propyl) acrylate, 2- (2'-methacryloxy-5'-methylphenyl) benzotriazole. In the context of the present invention, all of these compounds are suitable but the Applicant has more particularly used MOBP insofar as it has been handling this UV filter for many years, for the manufacture of silicone intraocular lenses.

The monomers, UV filters, generally intervene at a rate of 0.5 to

5 parts by weight, advantageously from 0.5 to 2 parts by weight, in the mixture of monomers, precursor of the poly (HEMA / EMA) copolymer, original constituent of the intraocular lenses of the invention (per 100 parts by weight of monomers: HEMA + EMA). In the above paragraphs, reference has been made to a crosslinking agent and a UV filter, since the intervention of a single additive of each of these two types of additive is preferable, for a simplification of the final formulation. It is obviously not in any way excluded from the scope of the present invention to involve a mixture of at least two additives of each of these two types ... or even to involve a single additive, capable of performing both functions.

The crosslinked poly (HEMA / EMA) copolymer, constituting at least the optics of the intraocular lenses of the invention is, in fact, advantageously obtained by copolymerization of the following monomers: the main monomer: HEMA, generally occurring at the right level from 77.5 to

87.5 parts by weight (advantageously 80 to 85 parts by weight); the comonomer: EMA, generally intervening at a rate of 12.5 to 22.5 parts by weight (advantageously 15 to 20 parts by weight); said main monomer and comonomer, (HEMA + EMA) intervening for 100 parts by weight; the crosslinking agent, such as EDMA: intervening, as an additive, in an effective amount (generally between 0.5 to 5 parts by weight and advantageously between 0.5 and 2 parts by weight); and advantageously, the UV filter, such as MOBP, intervening, as an additive, in an effective amount (generally between 0.5 to 5 parts by weight, and advantageously between 0.5 to 2 parts by weight). the parts by weight indicated above for the crosslinking agent and the UV filter are given per 100 parts by weight of the main monomer and comonomer: HEMA + EMA. According to a particularly preferred variant, said crosslinked copolymer is obtained with 82.5 parts by weight of HEMA and 17.5 parts by weight of EMA.

We have previously seen that the intraocular lenses of the invention can be monobloc or composite. According to the first variant, their optics and their haptics is therefore in a poly (HEMA / EMA) copolymer, as defined above (generally the same, but it is not excluded from the scope of the invention that two copolymers of this type are associated). According to the second variant, only their optical is in such a poly (HEMA / EMA) copolymer. Their haptics is made of a different material, which obviously is compatible with their optics and does not compromise the biocompatibility, flexibility, or generally the mechanical and optical properties of the assembly ... According to a preferred embodiment of this second variant , the intraocular lenses of the invention combine an optic in said poly (HEMA / EMA) copolymer and a haptic in polyMMA.

We now come to the second object of the present invention, namely the process for preparing intraocular lenses as described above. Said method comprises:

the preparation of at least one block of crosslinked poly copolymer (HEMA / EMA) by copolymerization of a mixture of HEMA and EMA monomers in the presence of effective amounts on the one hand of a polymerization initiator and on the other hand d 'a crosslinking agent and advantageously a UV filter whose chemical formula contains at least one reactive function;

- Cutting the optics or even the optics and haptics of said intraocular lens in said block of copolymer.

Said method is generally implemented according to one or the other of the two advantageous variants specified below. According to the first advantageous variant, a single block of crosslinked poly (HEMA / EMA) type copolymer is used. The intraocular lens (optical + haptic) of the invention is cut (size) from said block. Said one-piece lens thus cut is generally then milled, in order to optimize its surface condition. According to the second advantageous variant, a single block of crosslinked poly (HEMAΕMA) copolymer is also used. From this, the optics of intraocular lenses of the invention are produced. On said optic, in crosslinked poly (HEMA / EMA), it is then possible to report, in a manner known per se, a haptic in a different material, of another type (for example, in polyMMA). One can also prepare an intraocular lens of the invention of this type - composite lens whose optics are typically made of poly (HEMA / EMA) and the haptics of a material of another type - according to the technique described in patent application EP-A-0 734 319.

Furthermore, the preparation of intraocular lenses of the invention “monoblock” cannot be totally excluded according to the above techniques for the preparation of composite lenses, from two blocks of copolymers. different, both of the crosslinked poly (HEMA / EMA) type. In one of said blocks, the optics of said intraocular lens are cut, in the other one the haptics are cut ... In general, the block of suitable material is obtained (or even the blocks of suitable materials are obtained) by copolymerization in a mold of a reaction mixture typically containing the HEMA and EMA monomers. Said reaction mixture also contains, as indicated above:

an effective amount (generally from 0.5 to 5 parts by weight and advantageously from 0.5 to 2 parts by weight, per 100 parts by weight of monomers: HEMA + EMA), of a crosslinking agent, such as EDMA. Said EDMA can in particular intervene at a rate of 0.8 parts by weight. Other crosslinking agents, as indicated above, can intervene in place of said EDMA;

- And, advantageously, an effective amount (generally from 0.5 to 5 parts by weight, advantageously from 0.5 to 2 parts by weight, per 100 parts by weight of monomers: HEMA + EMA) of a UV filter, such the MOBP. Said MOBP can in particular intervene at a rate of 1 part by weight. Other UV filters, as indicated above, can intervene in place of said MOPB.

Said reaction mixture also conventionally contains at least one radical polymerization initiator. Those skilled in the art are aware, in fact, that the polymerization of acrylics requires, for its initiation, a source of free radicals. As initiator of radical copolymerization

HEMA-EMA according to the invention, it is possible in particular to use:

- a mixture of sodium phosphite and sodium phosphate (or any other redox couple);

- an azo compound, such as azobisisoburyronitrile (AIBN) or (2-2'-azobis (2,4-dimethyl valeronitrile) (AIVN), in particular marketed by the company WAKO under the reference V65, which is reproduced below the formulas developed:

CN CN

CH, CH,

I ³ I ³

CH, CH CH; —C N = N C CH, —CH CH, AIVN

³ I ^Λ II ² I

CH ₃ CN CN CH ₃

The latter compound is particularly preferred in view of its low toxicity, as well as that of its degradation products. (It should however be noted, in general, that said polymerization initiator intervenes in very small quantities and is generally eliminated at the end of the process for preparing the intraocular lenses of the invention); - a peroxide, such as benzoyl peroxide.

A person skilled in the art knows how to control the amount of intervention of said radical polymerization initiator (generally less than 1 part by weight, per 100 parts by weight of monomers: HEMA + EMA) and in general the kinetics of polymerization of the reaction mixture. He knows in particular that, the oxygen neutralizing the action of said polymerization initiator, it is highly preferable to eliminate it from the reaction mixture before the temperature rise. Bubbling of inert gas of said reaction mixture is strongly recommended. Regarding the heating program, its optimization is within the reach of the skilled person.

Regarding the preferred intervention ratios of the main reagents: HEMA and EMA monomers, they have been specified upstream in this text. The intraocular lenses of the invention combine, as already specified above, good optical and mechanical properties. They may in particular have resistance to rupture of between 3 and 3.5 MPa, entirely comparable to that of the intraocular silicone lenses that the Applicant markets. The invention is illustrated by the example below. Its interest is highlighted by the advanced results of a "comparative study":

- IOL of the invention: poly (HEMA / EMA)

- IOL of the prior art: poly (HEMA / MMA). Making an IOL of the invention

82.5 g of hydroxyethyl methacrylate (HEMA), 17.5 g of ethyl methacrylate (EMA), 1 g of 4-methacryloxy-2-hydroxybenzophenone (MOBP) were poured into a beaker. g of ethylene glycol dimethacrylate (EDMA) and 0.2 g of benzoyl peroxide.

The reaction mixture was homogenized and then bubbled with argon for 2 min. The solution thus deoxygenated is then distributed in molds; said molds are then placed:

- 48 hours in a water bath at 40 ° C;

- 48 hours in a water bath at 60 ° C;

- then 48 hours in an oven at 100 ° C.

The material obtained, after cooling, is removed from the mold. It is then rinsed, cut and then milled to give an intraocular lens of the invention. Said material has a breaking strength of 3 MPa.

Manufacture of an IOL of the prior art

The Applicant wanted to prepare an IOL whose material (poly (HEMA / MMA)) has an identical breaking strength (3MPa). This result was obtained by carrying out the polymerization described in the previous paragraph with:

83.2 g of hydroxyethyl methacrylate (HEMA)

16.8 g of methyl methacrylate (MMA).

Properties of said IOLs

The results obtained are given in the table below:

Mo ue average asticit. They clearly show the interest of the invention. For an equivalent (acceptable) breaking strength, the material with EMA is:

- more flexible,

- has a higher refractive index (this makes it possible to produce optics of the same power which have smaller thicknesses);

- has a lower water content and expansion coefficient;

- has a greater elongation at break.

Claims

claims

1. Intraocular lens, having an optic and a haptic, a flexible hydrophilic acrylic material constituting at least said optic, even said optic and said haptic; said lens being characterized in that said flexible hydrophilic acrylic material is a crosslinked copolymer of hydroxyethyl methacrylate (HEMA) and ethyl methacrylate (EMA).

2. Intraocular lens according to claim 1, characterized in that said crosslinked copolymer contains the units [HEMA] and [EMA] in a ratio: R = p ï fTi; ledi ratio R being between 3.0 and 6.1, advantageously between 3.5 and 5 and being, according to a particularly preferred variant, 4.1.

3. Intraocular lens according to one of claims 1 or 2, characterized in that said crosslinked copolymer contains an effective amount of a UV filter, linked to its skeleton.

4. Intraocular lens according to any one of claims 1 to 3, characterized in that said crosslinked copolymer is obtained by reaction, per 100 parts by weight of monomers: HEMA + EMA, of:

. 77.5 to 87.5, advantageously 80 to 85, parts by weight, of HEMA and

. 12.5 to 22.5, advantageously 15 to 20, parts by weight, of EMA, in the presence of an effective amount of a crosslinking agent and, advantageously, of an effective amount of a UV filter, the chemical formula contains at least one reactive function. 5. Intraocular lens according to claim 4, characterized in that said crosslinked copolymer is obtained by reaction of 82.5 parts by weight of HEMA and 17,

5 parts by weight of EMA.

6. Intraocular lens according to any one of claims 1 to 5, characterized in that its haptic is made of a hydrophobic material such as polymethyl methacrylate (polyMMA).

7. Method for preparing an intraocular lens according to any one of claims 1 to 6, characterized in that it comprises:

the preparation of at least one block of crosslinked poly copolymer (HEMA / EMA) by copolymerization of a mixture of HEMA and EMA monomers in the presence of effective amounts on the one hand from an initiator of polymerization and on the other hand of a crosslinking agent and advantageously of a UV filter whose chemical formula contains at least one reactive function;

8. Method according to claim 7, characterized in that the monomers HEMA and EMA intervene at a rate: from 77.5 to 87.5, advantageously from 80 to 85 and particularly preferably from 82.5, parts by weight of HEMA and from 12.5 to 22.5, advantageously from 15 to 20 and particularly preferably from 17.5, parts by weight of EMA, per 100 parts by weight of the mixture of monomers: HEMA + EMA.