FR2682959A1 - WETABLE BIOCOMPATIBLE MATERIALS BASED ON SILICON ELASTOMER AND PROCESS FOR THEIR PRODUCTION. - Google Patents

Abstract

Wettable 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 having epoxy functions, and protide wettability molecules which are chemically bonded to the substrate surface by grafting them onto said epoxy functions of the elastomer.

Description

WETABLE BIOCOMPATIBLE MATERIALS BASED ON ELASTOMER
SILICONES AND METHOD FOR THEIR PRODUCTION
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 permeability to oxygen, 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 exhibit directly the wettability properties required in the tear medium. It has indeed 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. 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 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, by approaching the natural conditions of maintenance of the tear film on the cornea, in order to better stabilize the tear film, avoiding fouling and increasing the longevity of contact lenses. It results from the discovery that, against all expectations, grafted saccharide molecules are not sufficient to meet the demand for biocompatibility in the ocular medium, whatever the high wettability that a large number of hydroxyl groups thus brought to the surface of the material may allow.

 The invention therefore proposes to use as self-supporting substrate epoxidized silicones in the mass, but by grafting onto it, no longer polysaccharides, but high molecular weight amino acid molecules of the protein type, such as polypeptides or proteins. , closer to the constituents of human tissue.

 It should be recalled that if reference is made to applications other than the manufacture of contact lenses, where the materials are nevertheless required to also exhibit biocompatibility and wettability properties in contact with human tissue, it is possible to observe that collagen has already been used, but in a different context where the substrate was metallic or ceramic, like the materials used in bone implants. In this case, the collagen, possibly denatured or fixed by glutaraldehyde, was used as a coating on the substrate, optionally pretreated with a mono-molecular layer of polysiloxane as described in the US patent 4,652,459. find there a similarity with the elastomers of epoxidized silicones in the mass to which the present invention is specifically intended.

 In the context of the invention, the grafting of an appropriate compound to the surface of a self-supporting substrate poses specific problems which the prior art has not been able to resolve. In particular, insofar as one uses a polymer of epoxidized silicones, it is desirable that this substrate retains the flexibility and transparency properties of the silicones without being kind in the article finished 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.

 From this point of view, it has appeared, in accordance with the present invention, that it is possible to obtain results superior to those which were previously sought in hydrophilicity as high as possible, by taking advantage of the specific structure of proteins. and similar amino acids.

 The present invention therefore relates to wettable 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 crosslinkable organopolysiloxane composition comprising functions epoxy in its bulk, and protein wetting molecules chemically bonded to the surface of said substrate by grafting onto said epoxy functions of the elastomer.

 The invention also relates to a process for the preparation of an article made of wettable organic material, biocompatible in the ocular medium, characterized in that it consists in bringing a self-supporting substrate of epoxidized silicone into contact with a solution of a protein compound. for fixing on the surface of said substrate protein wetting molecules by grafting onto epoxy functions of said substrate, so as to confer on said article the ability to ensure a permanent renewal of the tear film without however covering its surface in a leaktight manner.

 The term “protein molecules” is understood to mean here all natural or artificial molecules resulting from the condensation of amino acids, which includes polypeptides, compounds having a sequence of at least two peptide functions, and the proteins which are in particular the natural proteins, albumin, transformation proteins, coagulated or more or less hydrolyzed, scleroproteins.

 Without wishing to give a limiting interpretation to the reaction phenomena which can occur when the epoxidized silicone is put in the presence of the protein molecule, it seems that the latter binds chemically to the substrate either by acid or amine functions remaining free at the end of a chain of weakly condensed amino acids or simple polypeptides, either on one or the other of the reaction groups which may comprise compounds of more complex formula, such as the amine groups -NH2 (primary or secondary), acid -COOH, alcohol (hydroxyl -OH), aldehyde -CHO, ketone -CO, and all the precursors of such reaction groups.

In accordance with the invention, it is possible to use, as protein compounds, polypeptides whose formula results from the condensation of at least two amino acids, in particular of 3 or 4 amino acids, and whose molecular weight is of the order of 100 to 400 daltons. Such compounds are then advantageously used under conditions suitable for involving rather the amine-type reaction groups in the grafting reaction on the epoxy functions of the substrate, or at least allowing at least one free carboxylic acid group to remain. at the end of the chain of the grafted molecule. To do this, a basic medium, at a pH in particular between 8 and 14, and preferably between 9 and 13, is generally suitable.
Optionally, the actual grafting operation can advantageously be completed by an acid treatment which quaternizes the amine attached to the substrate and thus releases the acid. in case a cyclization of the molecule would have occurred by the proton of the acid.

 According to another embodiment of the invention, it is nevertheless preferred to use polypeptides of higher molecular weight, linked by at least 5 peptides, because for molecular weights between, for example, 400 and 10,000, and which may range generally up to 40,000, it seems that the requirement for the presence of the carboxylic acid functions is then less.

 According to another characteristic of the invention, the compounds used to be fixed to the substrate of epoxidized silicones are chosen from the proteins which are present in the natural being in human tissues.

These can be more or less denatured or degraded, but they advantageously retain a molecular weight of at least 10,000. Furthermore, it seems that the best results in the context of the invention are obtained with fibrous proteins such as collagen , rather than with proteins like gelatin, or globular like lysosome, gamma globulins, albumins like ovalbumin.

 Among other things, collagen has the advantage of ensuring biocompatibility by the fact that it is commonly present in human tissue. We know that it has a structure comprising high molecular weight protein chains wound in a triple helix, from which undoubtedly results its fibrous nature.

 In the practical implementation of the invention, the substrate of epoxidized silicones previously used and hardened, for example by molding a transparent article such as a contact lens, is placed in the presence of an aqueous solution of the selected protein. This operation is preferably carried out by immersing the article in the solution.

 The concentration of the protein solution can be chosen at any value leading to sufficient fluidity to allow the contact necessary for the chemical reaction. From this point of view, a concentration of the order of 0.1 to 10% is generally desirable, with a preference for concentrations of between 0.5 and 3% for proteins such as gelatin or collagen.

 The reaction takes place at ordinary temperature or under slight heating, in particular at a temperature between 20 and 40 ° C. to achieve the desired objective and the ability of the lens to promote a renewal of the tear film, preventing its tearing. . It appeared preferable to carry out the reaction under mild conditions, in a slightly basic medium. In general, the pH of the protein solution during the treatment is preferably between 7 and 14, with a preference for a pH of the order of 8 to 10.

 It can be seen that under these conditions the appropriate grafting is ensured in a reaction time of between 15 and 48 hours. The placing of the substrate in the presence of the solution is therefore preferably continued for a time of between 24 and 48 hours with stirring.

 In combination with the wettability molecules recommended according to the present invention, use is advantageously made of silicone compositions specially chosen to be suitable for producing elastomeric contact lens materials, on which wettability is ensured by surface grafting of said protein compounds onto epoxy functions remaining in the mass of the silicone elastomer resulting from the crosslinking of the essential constituents of the composition.

 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 of saccharide compounds, with 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 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 metal 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 organopolysiloxane with 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 hydrogen polysiloxane 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.

It should be noted, however, that we are talking here of the epoxy functions present in the uncured siloxane composition, while there remains only about 10% which has not reacted 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, having for example a molecular weight less than 400, whereas 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.

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 protein remains 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, which could be explained by the fact that that -These areas have hydrophobic properties in front of the grafting medium. More particularly in the preferred case of fiber molecules such as collagen, a sort of felt of tangled strands is formed.
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:
An epoxidized silicone contact lens (4.3 m / 100 g) is immersed for 24 h at room temperature in a 1% by weight solution of human IV collagen at pH 8.5. The epoxidized silicone is prepared as described in Example 1 of French patent No. 2 622 201 and shaped as also described in this patent.

 The agitation of the collagen 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 zone which would remain little or not sensitive to the reaction of the protein on the epoxy functions of the silicone substrate.

 The amount of collagen actually grafted is hardly measurable, but observations made on the grafted surface suggest that only a substantially mono-molecular form in a protein macro-molecule is fixed on the lens, which would explain that the properties intrinsic to the latter are in no way disturbed.

 After rinsing with water and conditioning in physiological saline (0.9% NaCl) the lens can be adapted to the eye of a patient. The tear film is stable and no fouling after several days of daily wear.

COMPARATIVE EXAMPLE ibis:
A non-epoxidized silicone contact lens (type 70 586 from RHONE-POULENC) is immersed for 48 h at room temperature in a solution at 1 r0 by weight of human IV collagen in distilled water, the pH of which is adjusted to 9 by soda.

 After rinsing with water and conditioning in physiological saline the lens is adapted. The tear film immediately tears.

 The comparison of these two tests shows the existence of a chemical fixation when the silicone carries epoxy groups. Indeed, a simple adsorption of collagen would not be sufficient to stabilize the tear film.

EXAMPLE 2:
An epoxidized silicone contact lens (4.3 meq / 100 g) is immersed for 48 h at room temperature in a 1% by weight solution of human placental collagen, pH 9.

 After adaptation on the eye of a patient it can be observed that the tear film is stable. No fouling is observed after several days of daily wear.

COMPARATIVE EXAMPLE 3:
A non-epoxidized silicone contact lens (type 70 586 from RHONE-POULENC) is immersed for 48 h at room temperature in a 1% by weight gelatin solution. After rinsing with water and packaging in physiological saline, the lens is adapted. The tear film immediately tears.

EXAMPLE 3
An epoxidized silicone contact lens (4.3 meq / 100 g) is immersed for 24 h at room temperature in a 1% by weight solution of gelatin of the high rigidity type, known under the trade name FLUKA 48 724, at pH 9, the DH being adjusted by dissolution of soda.

 After washing with water at room temperature, the lens is conditioned in physiological saline. The tear film is stable and fouling nonexistent after several days of daily wear.

EXAMPLE 4
An epoxidized silicone contact lens (4.3 meq / 100 g) is immersed for 24 h at room temperature in a 0.4% mucin solution at pH 10. After washing with water, the lens is conditioned in physiological saline. The tear film after adaptation remains stable.

 Naturally, the invention is in no way limited by the features which have been specified in the preceding examples or by the details of the particular modes of implementation chosen to illustrate the invention.

All kinds of variations can be made to the operating conditions as well as to the nature and proportions of the constituents and reagents without departing from the scope of the invention.

Claims (14)

 1. Biocompatible wettable organic materials 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 protein wetting molecules chemically bonded to the surface of said substrate by grafting onto said epoxy functions of the elastomer.  2. Biocompatible organic materials according to claim 1, characterized in that the said molecules have a sequence of at least two peptides having acid functions at the end of the chain.  3. Biocompatible organic materials according to claim 1, characterized in that said molecules are linearly linked polypeptides of at least 5 amino acids and have a molecular weight of at least 10,000.  4. Biocompatible organic materials according to claim 1, characterized in that said molecules are proteins.  5. Biocompatible organic materials according to claim 2 or 3, characterized in that the molecular weight of the polypeptides is between 400 and 40,000 daltons.  6. Biocompatible organic materials according to claim 1, characterized in that said protein molecules have a molecular weight of at least 400 daltons, in particular between 400 and 10,000.  7. Biocompatible organic materials according to claim 1, characterized in that said grafted molecules are protein molecules present in the natural state in human tissues, possibly degraded.  8. A method of preparing an article of material according to claim 1, characterized in that it consists in bringing into contact a substrate of epoxidized silicone shaped with a solution of a protein compound so as to graft on the surface of said substrate for protein molecules by grafting onto epoxy functions of said substrate in a proportion suitable for imparting the wettability property to said article, without however covering its surface in a leaktight manner.  9. Method according to claim 8, characterized in that proteins having a molecular weight of at least 10,000 are used as grafting compounds.  10. The method of claim 7, characterized in that collagen is used as protein grafted on the surface of the substrate.  11. Method according to any one of claims 8 to 10, characterized in that said protein solution is used at a concentration of the order of 0.1 to 10% by weight.  12. Method according to any one of claims 8 to 11, characterized in that said substrate is kept in contact with said solution for a time from 15 to 48 hours, the pH being between 7 and 14 and preferably from order of 8 to 10.  13. Method according to any one of claims 8 to 12, characterized in that said elastomer results from the crosslinking of organopolysiloxane containing from 1 to 10 meq of epoxy functions per 100 g of the siloxane constituents.  14. Use of the method according to any one of claims 8 to 13, and of the material obtained meeting the characteristics of any one of claims 1 to 7, as contact lenses, the organopolysiloxane composition being molded with suitable form for a contact lens and crosslinked by hardening prior to bringing the article obtained into contact with the solution of protein compounds.