WO1993009164A1

WO1993009164A1 - Biocompatible silicones for ocular use and method for producing same

Info

Publication number: WO1993009164A1
Application number: PCT/FR1992/000996
Authority: WO
Inventors: Claude Bourset; Jean-Claude Meslard
Original assignee: Essilor International (Compagnie Generale D'optique)
Priority date: 1991-10-29
Filing date: 1992-10-26
Publication date: 1993-05-13
Also published as: FR2682958A1; AU2948392A

Abstract

Biocompatible organic materials for ocular use comprising a combination of a self-supporting substrate made of epoxy silicone elastomer obtained by cross-linking a cross-linkable organopolysiloxane composition comprising epoxy functions, and wettability molecules which are chemically bonded to the substrate surface by grafting them onto said epoxy functions of the elastomer, the grafted molecules having free carboxylic acid terminal groupings.

Description

BIOCOMPATIBLE SILICONES IN EYE MEDIA AND THEIR MANUFACTURING METHOD

The present invention relates to a silicone elastomer grafted on the surface to constitute a biocompatible material of good wettability, such that it is useful in particular for the manufacture of contact lenses. However, the silicone elastomers grafted according to the present invention can be used for any other application requiring the same qualities, such as implants for replacing elements of the human body, and there more particularly, intraocular implants.

Among the organic compositions which are currently proposed for constituting transparent materials suitable for the manufacture of contact lenses, silicone elastomers are enjoying increasing success. These are polymers of the organo-polysiloxane type which, in addition to satisfactory mechanical and optical properties, have the advantage of a high permeability to oxygen, which is sufficient to preserve the gas metabolism of the cornea without it is necessary, as in the case of hydrogels based on hydroxyethyl methacrylate or similar compounds, that the materials contain significant amounts of water.

Difficulties have arisen, however, in the use of conventional polyorganosiloxane compositions, known to be capable of being molded and hardened in the form of contact lenses or intraocular implants, when it has been found that they do not have directly the wettability properties required in the tear medium. It has in fact been revealed that the silicone compositions harden into elastomers with hydrophobic surface, which should be made hydrophilic without altering their optical characteristics and their mechanical properties. It was then that various treatments were proposed aimed at modifying the properties of surface of articles resulting from the shaping and hardening of such compositions, so as to obtain a material having the desired wettability.

Various techniques for modifying surface properties have been proposed successively, as is recalled in European patent n ° 0 317 377 and the French patent application published under the number 2 622 201. However, these techniques did not make it possible to avoid fouling material by proteins of the lachrymal medium, resulting opa ^{'pecification} and the disappearance of the wettability. It was therefore proposed, in accordance with these patents, to use special silicone compositions, containing epoxidized silicone oligomers, thanks to which it became possible to graft on the surface of the material resulting from their crosslinking, an organic compound of the family of sugars.

The present invention aims to further improve these techniques, for the purpose of better stabilization of the tear film, avoiding fouling and increasing the -longevity of contact lenses.

It proposes for this to use a self-supporting substrate made of epoxidized silicone elastomer in the mass, as previously, but by grafting on it no longer polysaccharides, but molecules chosen to preserve free carboxylic acid groups after the grafting reaction.

The grafting of an appropriate compound onto the surface of a substrate poses specific problems in the context of the invention. In particular, insofar as an epoxidized silicone polymer is used, it is desirable for this substrate to retain the flexibility and transparency properties of the silicones without being hampered in the article finished by the presence epoxy functions, even though such epoxy functions are more commonly used to obtain properties grip. On the other hand, we thus treat articles of small dimensions (of the order of 1 to 2 cm in diameter and 1 to 3 mm in thickness) whose shape, surface uniformity and a biocompatibility with the ocular medium such that it gives them the capacity to ensure a permanent renewal of the tear film.

Surprisingly, it has been observed that the presence of acid groups (-C00H) on the surface of the finished article in epoxidized silicone considerably improves all of the qualities thereof, and in particular those required by biocompatibility in ocular medium, whereas previously, the main objective was to obtain wettability by the multiple alcohol groups (-0H) of the sugars. It was notably possible to verify that the solution proposed by the present invention is entirely suitable for obtaining the desired wettability properties, but also for avoiding tearing of the tear film when using these articles as contact lenses and delaying thus their fouling, as well as to avoid opacification which constitutes the major drawback of the prior techniques in the case of intraocular implants.

The invention therefore essentially relates to organic materials biocompatible in the ocular medium, characterized in that they comprise in combination a self-supporting substrate of epoxidized silicone elastomer resulting from the crosslinking of a composition of crosslinkable organopolysiloxanes comprising epoxy functions in its bulk, and molecules chemically linked on the surface of said substrate by grafting onto said epoxy functions of the elastomer, said molecules having, after grafting, free terminal groups of carboxylic acid.

The invention also relates to a process for the preparation of a biocompatible article in an ocular medium with base of a silicone elastomer, characterized in that it consists in bringing a self-supporting substrate of epoxidized silicone into contact with a solution of an organic compound whose molecules have at least one reaction group with regard to the epoxy functions, performing a surface grafting of said substrate, and at least one terminal acid group remaining in the form of free carboxylic acid on the grafted molecules.

The reaction groups ensuring by grafting the chemical fixation of the molecules on the epoxidized silicone can be very diverse, including where appropriate the carboxylic acid groups. So we will mention here the amino groups -NH _? (primary or secondary), -C00H acid, alcohol - OH, aldehyde -CH0, ketone -GO, and all the precursors of such reaction groups. The conditions of the grafting reaction are adjusted accordingly, so as not to involve at least one carboxyl group in the molecule, which must remain free or ^" capable of being released on the grafting compound. This implies" for example that a only acidic compound must be at least diacid, and an acid-amino or acid-alcohol compound will preferably be used in a sufficiently basic medium to promote the fixation of -OH or -NH2 on the epoxidized silicone, especially if it only presents '' an accessible carboxyl group per molecule.

In accordance with the invention, it is preferred in this regard to use compounds which deviate from those of the family of sugars (or carbohydrates) such as glucose, by the fact that, for relatively low molecular weights, is generally less than 400 , they are not cluttered with specifically hydrophilic groups, the number of hydroxyl groups being, for example, restricted to no more than three per six carbon atoms.

According to another selection criterion, an acid-alcohol type grafting compound has an acid functionality at least equal to its alcohol functionality, therefore a number of carboxyl groups -C00H at least equal to the number of hydroxyls which it contains per molecule.

The method according to the invention extends to the use of amino acids which are protein molecules, in particular denatured natural proteins, artificial proteins, and polypeptides consisting of a chain of at least 2 amino acids. It seems that the use of proteins of this type, with free acid function at the end of the chain, allows. simultaneously take advantage of the particular structure of the polypeptides and proteins, to obtain an action favorable to the permanent renewal of the tear film which the mere presence of the terminal carboxyl groups would not be sufficient to explain. The most useful polypeptides here have a molecular weight between 100 and 400 daltons, because for complex molecules of high molecular weight, of the order of 10,000 to 40,000, and especially for proteins of even higher molecular weight, it It seems that the requirement for the presence of the carboxyl functions at the chain end has only a negligible impact on the properties of the finished product.

In combination with the graftable compounds recommended according to the present invention, it is advantageous to use silicone compositions specially chosen to be suitable for the production of elastomeric materials of ocular lenses, on which the wettability and the biocompatibility in the ocular medium are ensured by grafting of said surfaces. compounds on epoxy functions remaining in the mass of the silicone elastomer resulting from the crosslinking of the essential constituents of the composition, the grafting being carried out under conditions preserving the terminal acid groups of these compounds.

The silicone compositions are therefore preferably chosen from those which have already been described and claimed by the applicant with a view to achieving wettability by grafting saccharide compounds, with particular reference to European patent No. 0 317 377, to the corresponding American patent No. 4 940 751 and to Patent application No. 89 05363 published under No. 2,646,672.

Such compositions are characterized in that they comprise at least two crosslinkable organopolysiloxane type constituents, at least one of which comprises vinyl groups attached directly to a silicon atom and of which at least one second comprises silyl groups in substantially stoichiometric proportions relative to the reaction of the Si-vinyl groups with the Si-H groups, or more particularly, proportions of the order of 0.5 to 4 moles of Si-H group for one mole of vinyl groups in the total of the composition, at least one of the crosslinkable siloxane constituents further comprising substituents with an epoxy function, in the proportions which have already been indicated.

Such a composition also contains, as is conventional, a catalyst promoting the crosslinking of organopolysiloxanes in sufficient proportions to ensure the catalytic effect on the polyaddition reaction SiH + Si-vinyl. Conventional catalysts include metallic catalysts, the metal of which is chosen from platinum, palladium, nickel, rhodium, ruthenium, but also basic catalysts of alkali or alkaline-earth metals (in the form of hydroxide for example), the latter generally having the advantage of not degrading the epoxide functions of the epoxide oligomer present in the crosslinkable composition.

It also appears from the preceding patents that one of the siloxane constituents of the composition preferably comprises at least three silyl groups per molecule, on silicon atoms each linked to a single hydrogen atom, and that another of said constituents carries at least two vinyl groups per molecule, with a preference for organo-polysiloxanes with chain blocked at both ends by a vinyl motif.

In practice, the preferred epoxidized silicones for the implementation of the invention, formed and prepared as described in French Patent No. 2,622,201, result from the polymerization of an epoxidized silicone resin composition containing functional groups. epoxy in a proportion of between 0.05 and 15 meq per 100 g of the constituents of the resin. Preferred compositions obtained from a mixture of an organo-polysiloxane component with chains blocked by vinyl di-organo siloxy units and at least one hydrogenopolysiloxane component with epoxy functions comprises, in the uncured composition, l '' from 1 to 10 meq of epoxy functions per 100 g of the siloxane constituents. Note, however, that we are talking here of the epoxy functions present in the uncured siloxane composition, while only about 10% of it remains unreacted after polymerization and crosslinking of the resin.

In the practical implementation of the invention, the self-supporting substrate of epoxidized silicone previously shaped and hardened, for example by molding and crosslinking polymerization, into a transparent article such as an ocular lens, contact lens or implant intraocular, is placed in the presence of an aqueous solution of the graftable organic compound chosen under conditions suitable for promoting the desired grafting reaction. This operation is preferably carried out by immersing the article in the solution.

The concentration of the solution of graftable compound can be chosen at any value leading to a fluidity sufficient to allow the contact necessary for the chemical reaction. From this point of view, a concentration of between 0.1 and 50% by weight can generally be used in the case of compounds of relatively simple formula, for example having a molecular weight of less than 400, while for compounds of high molecular weight, it may be preferable to keep concentrations within the limits of 1 to 10 by weight. In total, it is most often desirable to carry out a concentration of between 1 and 20 by weight, with a preference for concentrations of between 5 and 15% by weight.

The reaction takes place at room temperature or at a temperature up to the boiling point of the solution, gentle heating is often desirable, and useful reaction times can vary from minute to 2 days. In general, we will have to seek a compromise between the concentration of the solution, which can increase the cost of the process in the case of expensive compounds, and an extended contact time. Furthermore, provision may be made to carry out the reaction in a solvent medium in order to increase the temperature beyond 100 ° C. when this appears advantageous depending on the compound to be grafted.

The most significant element of the reaction conditions concerns the choice of the pH of the solution of the compound to be grafted, because it is he who appeared to be the most determining on the nature of the functional groups involved in the grafting reaction on the epoxide functions. of the substrate. In general, an acidic medium, therefore with a pH of between 1 and 6, and preferably of the order of 3 to 4, will be used to fix the compounds via aldehyde or ketone reaction groups, forming therefore acetal bonds by condensation on the epoxy functions of the compound, always with the aim of leaving free the carboxyl group or groups which the same compounds also contain. On the contrary, one will advantageously choose a basic medium, therefore a pH of grafting solution of between 8 and 14, and preferably between between 9 and 13, in the case of compounds to be grafted with a labile hydrogen group, such as groups of alcohol (hydroxyl), amino type, or their precursors, so as to form an ether or amine bond.

As already pointed out, the beneficial results obtained according to the invention require the use of a graftable compound which has terminal carboxyl groups at the end of the treatment.

For this purpose, it _. it is sometimes necessary to release these groups after the grafting operation. This is the case in particular when the grafting is carried out in basic medium and involves the amino group of an amino acid of relatively simple structure, when when returning to neutral or acidic medium, the proton of the acid risks being attracted by the nitrogen of the amino bond with the substrate, so that the molecule closes on itself in a zwitterion. An appropriate solution to avoid this cyclization consists in passing it through immersion in an aqueous solution of a strong acid, such as hydrochloric acid, which tends to protect the nitrogen by quaternization, so that the acid grouping of the molecule remains definitively free.

At the end of the treatment, it has been observed that although the starting substrate is epoxy in the mass, over a thickness at least of the order of 0.3 mm for example, the grafted compounds remain on the surface, without penetrating further. only over a thickness of a few tens of microns, or 10 to 50 microns. At the very least, it seems that thanks to the choice of grafting agent, in combination with the material of the substrate, the grafted compound does not diffuse inside the substrate and that it remains in a practically monomolecular layer on the surface. of the substrate, which could be explained by the fact that the latter retains zones with hydrophobic properties in front of the grafting medium. Thus, hydrophilic sites corresponding to the lens would be preserved while obtaining a very fine and regular distribution on the substrate surface between hydrophilic and hydrophobic sites. This good distribution would also ensure the continuity and regularity of the monomolecular layer, such a layer would avoid untimely variations in the voltage-activity at the surface of the lens and thereby considerably reduce the tear film tear phenomena observed for the lenses used. previously.

The thickness of the monomolecular layer would be thin enough so that it does not disturb the properties of the lens such as its dimensional and optical properties or even its surface condition.

This fine and regular distribution of hydrophilic and hydrophobic sites would be ensured by individual positioning of the relatively short molecules. In the case of longer molecules, it would be ensured by the positioning at several fixing points of the. olecule on the surface of the lens.

By way of preferred compounds for the implementation of the invention, the following compounds should be mentioned more particularly, distinguishing those which the process according to the invention uses in a rather acid medium according to the nature of the functional group caused to react with the epoxy functions of the silicone substrate:

Compounds for implementation in basic medium, leading to recommending a reaction time of 1 minute to 2 days, preferably of the order of 24 to 48 hours, and a temperature of 20 to 75 ° C:

Hydroxy acids:

Monoacids:

- hydroxy acids of formula 0H (CH ₂ ) C00H, where n is an integer between 1 and 8, with for example glycolic and hydroxypropanoic acids, hydroxybutyric,

- precursors of these acids, in particular the lactones of formula: - 0- (CH) _n -C0 -

with examples: _{proplolactone> b} utyrolactone, caprolactone.

- aromatic hydroxy acids of formula:

HO CGH, ^(c H _²⁾ _n - ^C00H where n is ^integer between 1 and 8, for example the hydroxy-benzoic acid or phenylacetic acid hydroxy.

Polyacids: for example: ^' N- (2-hydroxyethyl) ethylene diamine triacetic acid, citric acid, tartaric acid.

Amino acids

Monoacids:

- amino acids of formula H dN <CH2 ") n-C00H, where n is an integer between 1 and 8, with for example: glycerin, / 3-alanine, 4-amino butyric acid, 6-amino caproic acid, amino-8 caprylic, amino-11 undecanoic.

- precursors of these acids, in particular the lactams of formula - N- (CH ά „) n -C0 -

with for example:, bu, t.yrol, act_.ame, caprol-, actame ...

-branched amino acids: H N-CH-C00H

² IR

(where R is an alkyl radical of 1 to 5 carbon atoms), for example: alanine, 2-amino butyric acid, phenylalanine, hydroxyproline, threonine.

Polyacids: for example, aspartic acid or glutamic acid

Aromatic compounds: for example: 4-amino acid benzolque, acid 5-amino isophthalic.

Compounds for use in an acid medium, leading to recommending a reaction time of a few hours, preferably of the order of 2 hours, and a temperature of 80 to 105 ° C:

Aldehyde or ketone functional acids, whether aliphatic or aromatic, a general formula being: R- (C0) -Z-C00H where R is H or CH ^ and Z is a lower alkylene radical, comprising in particular of 1 to 6 carbon atoms, or an aromatic radical such as the phenylene radical.

For example: carboxy benzaldehyde acids, levulinic.

Ester acids such as acetyl butyric.

The invention will now be described in more detail in the context of specific examples of implementation which are in no way limiting.

EXAMPLE 1: a contact lens made of epoxidized silicone elastomer, manufactured and shaped as described in Example 1 of French Patent No. 2,622,201 from a composition comprising 4.3 meq. of epoxy functions per 100 g of crosslinkable siloxane oligomers, is immersed in a solution at 10% by weight of 4-hydroxy butyric acid at pH 13.

During this treatment, permanent stirring of the solution in contact with the lens is maintained by going back and forth vertically, while preventing the lens from touching the walls of the container containing the assembly. One can thus ensure a uniform grafting without shadow or contact area which would remain little or not sensitive to the grafting reaction on the epoxy functions of the silicone substrate. After 24 hours of immersion at room temperature, the lens is rinsed with water, then using a saline solution, buffered to pH 7. The preservation is carried out in a buffered saline solution. After several weeks of daily wear, no trace of fouling is visible.

EXAMPLES 2 to 4:

Lenses are treated with various acids under the conditions of Example 1 with other hydroxylated mono- or poly-acids. ^'

The self-supporting substrate is the same and the grafting treatment is also carried out in a basic medium.

^• The results are reported below: No. acid wettability movie encras- to tear water sow

2 stable no

3 stable no 4

stable less than

30% of cases

EXAMPLE 5

A lens identical to that of Example 1 is treated with a 10% solution by weight of glycolic acid at pH 13 for 24 h at room temperature. The lens thus treated is rinsed with water, then with a saline solution, buffered to pH 7, before being stored in a buffered saline solution.

After adaptation on the eye of a patient, it can be observed that the tear film is stable, and if a slight fouling appears after several days of daily wearing, it nevertheless remains much weaker than with an untreated lens.

EXAMPLES 6 to 1;

Lenses identical to those of Example 1 are treated with amino acids under the same conditions as in Example 5. The results are reported below: n ¹ wettable acid film fouled with rymal lake seed

6 aspartic- ^". Yes

7 glutamic yes 8 threonine yes

9 2-amino butyric yes

10 4-amino butyric yes

11 Glycylglutamic yes

It appears from these results that the simple amino acids ensure the stability of the tear film, but do not make it possible to avoid fouling perfectly during prolonged wearing. However, ^one example below shows that the positive results which the invention can be achieved through further processing of releasing acid groups by quaternization of the amine.

EXAMPLE 12:

An epoxidized silicone contact lens identical to that of Example 1, is treated for 24 hours at room temperature in a solution of 10 4-amino butyric acid at pH 13.

After rinsing with water, the lens is immersed for 5 min in an HCl solution in order to quaternize the amine. After rinsing with a saline solution buffered to pH 7, the lens is adapted to the eye.

The tear film is stable and there is no visible fouling.

EXAMPLE 13:

A lens identical to that of Example 1 is treated with a solution at 10% by weight of butyrolactone at pH 13 for 24 h at room temperature. After rinsing in a saline solution and adaptation, the tear film is stable and there is no visible fouling.

EXAMPLES 14 to 16:

An epoxidized silicone contact lens identical to that of Example 1 is treated for 2 to 4 hours at 105 ° C. in a 10% solution of a carbonyl acid. The corresponding pH is acidic, around 3 to 4.

The results are reported in the table below. acid number wettability time film encrusted with tear water

14 4-carboxy benzaldehyde 2 h yes stable no

15 acetyl butyric 2 h yes stable no

16 acetyl butyric 4 h yes stable no

Other compounds included in the general formulas presented above lead to similar results.

Claims

1. Biocompatible organic materials in the ocular medium, characterized in that they comprise, in combination, a self-supporting substrate of epoxidized silicone elastomer 5 resulting from the crosslinking of a composition of crosslinkable organopolysiloxanes comprising epoxy functions in its bulk, and wettability molecules chemically bonded to the surface of said substrate by grafting onto said epoxy functions. of the elastomer, in that 0 said molecules present, after grafting, end groups of free carboxylic acid, said molecules when they are of the acid-alcohol type, having an acid functionality at least equal to the alcohol functionality.

^J 2. Process for the preparation of a biocompatible article in an ocular medium based on a silicone elastomer, characterized in that it consists in bringing a self-supporting substrate of epoxy silicone into contact with a solution of an organic compound whose molecules have at least one reaction group with regard to the epoxy functions, under conditions such that a surface grafting of said substrate is carried out and at least one acid group remains in the finished material obtained in the form of acid free carboxylic.

3. Method according to claim 2, characterized in that said reaction group being of alcohol, amino or acid type, or a corresponding precursor, the grafting is carried out in basic medium.

4. Method according to claim 2, characterized in that said reaction group being of the aldehyde or ketone or ester type, the grafting is carried out in an acid medium.

5. Method according to claim 3, caracté¬ ized in that said compound is an amino acid of the type polypeptide having acid functions at the chain end and on the other hand amino functions capable of reacting with the epoxide functions of the organopolysiloxane of the composition.

6. Method according to any one of claims 2 to 5, characterized in that it comprises an additional acid quaternization treatment after grafting of said compound with an amino functional group.

7. A process according to any of claims 2 to 6, characterized in that said compound has a molecular weight of at most 400 daltons.

8. Method according to any one of claims 2 to 7, characterized in that said solution of graftable compound is used at a concentration of the order of 1 to 20% by weight.

9. Method according to any one of claims 2 to 8, characterized in that said elastomer results from the crosslinking of organopolysiloxane containing from 0.5 to 15, and preferably from A to 10 meq of epoxy functions for 100 g of the crosslinkable siloxane constituents.

10. Method according to any one of claims 2 to 9, characterized in that said substrate is kept in contact with said solution for a time from 1 minute to 48 hours, at a temperature of the order of 20 to 75 ° C for a basic medium at pH on the order of 9 to 13, or on the order of 80 to 105 ° C for an acid medium at pH on the order of 3 to 4.

11. Use of the method according to any one of claims 2 to 10 and of the material obtained meeting the characteristics of claim 1, as contact lenses, the organopolysiloxane composition being molded into the form suitable for a contact lens. and crosslinked by hardening prior to bringing the article obtained into contact with the solution of graftable compound.