FR2682958A1 - BIOCOMPATIBLE SILICONES IN EYE MEDIA AND THEIR MANUFACTURING METHOD. - Google Patents

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 PROCESS
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 replacement implants for 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 organopolysiloxane type which, in addition to satisfactory mechanical and optical properties, have the advantage of a high oxygen permeability, which is sufficient to preserve the gas metabolism of the cornea without it being 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 surface properties of the articles resulting from the shaping and hardening of such compositions, in order to thus obtain a material having the desired wettability.

 Various techniques for modifying surface properties have been proposed successively, as recalled in European patent no. O 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 of the material by the proteins of the lacrimal environment, resulting in clouding and the disappearance of 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, in order to better stabilize the tear film, avoiding fouling and increasing the longevity of contact lenses.

 It proposes for this to use a self-supporting substrate in silicone elastomer epoxidized in the mass, as previously, but by grafting 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 epoxy silicone polymer is used, it is desirable that this substrate retains the flexibility and transparency properties of the silicones without being hindered in the finished article by the presence epoxy functions, even though such epoxy functions are more commonly used to obtain adhesion properties. 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 (-COOH) 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 aim was to obtain wettability by the multiple alcohol groups (-OH) 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 thus delaying their fouling, as well as to avoid clouding which constitutes the major drawback of 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 mass, 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 based on 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, the molecules of which have at least one reaction group with respect to the epoxy functions, carrying out grafting on the surface 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. The amino groups -NH2 (primary or secondary), acid -COOH, alcohol will therefore be mentioned here
OH, aldehyde -CHO, ketone -CO, and all the precursors of such reaction groups. The conditions of the grafting reaction are adapted accordingly, so as not to involve at least one carboxyl group of the molecule, which must remain free or be able to be released on the grafted compound. This implies for example that an exclusively acidic compound must be at least diacid, and that an acid-amino or acid-alkocl compound will preferably be used in a sufficiently basic medium or to promote: fixation of -OH or -NH2 on the epoxidized silicone, especially if it has only one 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 an acid at least equal to its alcohol functionality, therefore a number of carboxyl groups -COOH at least equal. the number of hydroxyls it contains per molecule.

 The process 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 a free acid function at the top of the chain, makes it possible to 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 that the mere presence 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 end of the chain 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 an ocular medium are ensured by grafting of said surfaces. compounds on epoxy functions remaining in the bulk 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 resold by the applicant with a view to achieving wettability by grafting of saccharide compounds, with particular reference to European patent No. 0 317 377, to the American patent corresponding to 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 constituents of crosslinkable organopolysiloxane type, 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 epoxidized 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 is at least a carrier of two vinyl groups per molecule, with a preference for organo-polysiloxane with a chain blocked at the two 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 epoxide functions 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, of the order 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 intraocular implant, 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 weight high molecular weight, concentrations remaining within the limits of 1 to 10% by weight may be preferred. 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 above 100 ° C. when this appears advantageous depending on the compound to be grafted
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 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 9 and 13, in the case of compounds to be grafted by a labile hydrogen group, such as the groups of alcohol (hydroxyl) type, amine, 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 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 on return to neutral or acid medium, the proton of the acid risks being attracted by the nitrogen of the amine bond with the substrate, so that the molecule closes on itself in a zwitterion.

An appropriate solution to avoid this cyclization consists in passing by means of an immersion in an aqueous solution of a strong acid, such as hydrochloric acid, which tends to protect the nitrogen by quaternization, so that the grouping acid of the molecule remains permanently free.

 At the end of the treatment, it has been observed that although the starting substrate is epoxidized 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.

By way of preferred compounds for carrying out 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 brought to react with the epoxy functions of the silicone substrate
Compounds for use 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 OC
Hydroxy acids
Monoacids
- hydroxy acids of formula OH (CH2) nCOOH, where n is an integer between 1 and 8, with for example glycolic, hydroxypropanoic, hydroxybutyric acids,
- precursors of these acids, in particular the lactones of formula: -0- (CH2) n -CO
with examples: propiolactone, butyrolactone, caprol actone.

- aromatic hydroxy acids of formula
HO - C6H3 - (CH2) n -COOH
where n is an integer between 1 and 8, for example hydroxy benzoic acid or hydroxy phenyl acetic acid.

Polyacids
for example: N- (2-hydroxyethyl) ethylene diamine tri acetic acid, citric acid, tartaric acid.

Amino acids
Monoacids:
- amino acids of formula H2N (CH2) n-COOH, where n is an integer between 1 and 8, with for example: glycerin, ss-alanine, 4-amino butyric acid, 6-amino caprolque, 8-amino acid caprylic, undecanoic amin.

 - precursors of these acids, in particular the lactams of formula - N- (CH2) n -CO with for example: butyrolactam, caprolactam ...

-branched amino acids: H2N-CH-COOK
R (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 benzoic acid, 5-amino isophthalic acid.

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 OC:
Aldehyde or ketone functional acids, whether aliphatic or aromatic, a general formula being: R- (CO) -Z-COOH where R is H or CH3 and Z is a lower alkylene radical, comprising in particular from 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 particular 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 n0 acid wettability film fouling
with tear water
2 hydroxy proline yes stable no
3 citric yes stable no
4 tartaric yes stable less than 30%
cases
EXAMPLE 5:
A lens identical to that of Example 1 is treated with a 10% by weight solution 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 11:
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 n0 acid wettability film fouling
with tear water
6 aspartic yes stable light
7 glutamic yes stable no
8 threonine yes stable yes
9 2-amino butyric yes stable yes
10 amino-4 butyric yes stable yes
11 Glycylglutamic yes stable no
It appears from these results that the simple amino acids ensure the stability of the tear film, but do not make it possible to perfectly avoid fouling during prolonged wearing.

However, the example below shows that the good results targeted by the invention can be obtained by additional treatment for the release of 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 10% solution of 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 10% by weight solution 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.

n0 acid time wettability film foul
with tear water 14 carboxy-4
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 (11)

 1. 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 mass, and molecules wettability chemically bonded to the surface of said substrate by grafting onto said epoxy functions of the elastomer, said molecules having, after grafting, free carboxylic acid end groups.  2. Method for preparing a biocompatible article in an ocular medium based on 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, the molecules of which have at least one reaction group with respect to the epoxy functions, carrying out a grafting on the surface of said substrate, and at least one acid group remaining in the finished material obtained in the form of free carboxylic acid.  3. Method according to claim 2, characterized in that said reaction group being of alcohol, amine, 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, characterized in that said compound is an amino acid of the polypeptide type having acid functions at the end of the chain and on the other hand amine 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 acidic quaternization treatment after grafting of said compound with an amine functional group.  7. Method according to any one 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 1 to 10 meq of epoxy functions per 100 g of 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 OC for a basic medium with a pH of the order of 9 to 13, or of the order of 80 to 105 OC for an acid medium with a pH of 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.