Patent Application
20210369911
The present invention relates to crosslinkable and crosslinked compositions, as well as to a hydrogel obtainable from the crosslinked composition.
The present invention finds industrial applications in the field of biocompatible materials, and in particular that of ocular lenses.
In the description below, references in square brackets ([ ]) refer to the list of references at the end of the text.
A contact lens, worn on the eye, is used to correct vision defects such as myopia, astigmatism, or hyperopia. However, the human eye needs to maintain a certain level of hydration and oxygen circulation. Thus, the lens in contact with the eye must meet a set of specifications that include—but are not limited to—good oxygen permeability, good comfort, and hydrophilicity.
Contact lenses can be classified into two categories: rigid contact lenses, including rigid gas permeable lenses, and soft contact lenses, such as hydrogel or silicone hydrogel lenses.
During the production of polymer-based contact lenses, a polymerizable lens precursor composition is polymerized to form a crosslinked contact lens product, which can then be processed to form a hydrated contact lens. For example, the polymerizable precursor composition may be placed on a cavity of a contact lens-shaped mold, and may be polymerized therein to form a contact lens located in the cavity. Polymerization can be achieved by exposing the polymerizable composition by heating in the optional presence of thermal initiator or by exposure to ultraviolet light.
A hydrogel is a hydrated crosslinked polymer system that contains water in an equilibrium state. It is typically oxygen permeable and biocompatible, which makes it a preferred material for producing biomedical devices and in particular contact or intraocular lenses. Hydrogel soft lenses are manufactured from few basic monomers. Their choice will depend on the final properties that the lens manufacturer wishes to favor:
Often, conventional hydrogel contact lenses are the polymerized product of a composition of lens precursor(s) containing hydrophilic monomers such as 2-hydroxyethyl methacrylate (HEMA), methacrylic acid (MAA), methyl methacrylate (MMA), N-vinylpyrrolidone (NVP), but also optionally additives of polymeric nature such as polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) and combinations thereof. The precursor compositions also frequently contain one or more catalysts and one or more crosslinking agents.
Although these lenses provided some comfort, they did not provide sufficient oxygen permeability to prevent the problems associated with corneal hypoxia. Attempts to resolve this problem included copolymerizing HEMA with hydrophilic monomers such as methacrylic acid and N-vinylpyrrolidone. Although these polymers increase the level of oxygen permeability, the incorporation of these comonomers also leads to problems such as protein and lipid deposition, corneal dryness, and lens dehydration.
More recently, a new generation of polymers has been developed to further increase the oxygen level. These materials are based on the copolymerization of silicone or silane functionalized methacrylate co-monomers with hydrophilic co-monomers. Lenses produced from these materials were initially designed for extended use. Although they have succeeded in increasing oxygen permeability, these new materials still suffer from limitations such as lipid deposition and dry eye, which reduces eye comfort.
Moreover, current contact lenses made of silicone or PHEMA hydrogels are often associated with poor biocompatibility, as they trigger an immune response when biomolecules such as proteins, lipids, immunoglobulins and complement proteins bind to the lens surface. This reduces the stability of the tear film, causing the eye to feel dry.
One class of polymers for new contact lens materials is that of polyethylene glycol (PEG)-based polyurethanes, as described for example in the document EP2496620 ([1]), which illustrates a material comprising PEG diol, polyol, diisocyanate and polydimethylsiloxane (PDMS) diol. However, no lenses comprising this class of polymer are yet commercially available. There is thus a genuine need for new materials that overcome these defects, disadvantages and obstacles of the prior art, in particular having particularly attractive properties in terms of oxygen permeability, water content, resistance to water loss or retention, mechanical properties and strength (Young's modulus, stress and elongation at break), but also in terms of surface properties such as the coefficient of friction, surface roughness and wettability.
After substantial research, the Applicant has succeeded in developing a new material that meets the above-mentioned needs and is therefore particularly suitable for use in the manufacture of contact lenses.
Surprisingly, the Applicant has succeeded in creating a transparent hydrogel capable of swelling in an aqueous medium, and showing very attractive properties compared with existing materials, in particular by using polyglycerol, in particular hyperbranched polyglycerol, combined advantageously with other polyols and polyisocyanates.
Advantageously, the medical device is biocompatible, and in particular suitable for contact with the eyes, and hydrophilic. Furthermore, it has particularly attractive properties in terms of oxygen permeability, water content, resistance to water loss or retention, mechanical properties and resistance (Young's modulus, stress and elongation at break) but also in terms of surface properties such as the coefficient of friction, surface roughness and wettability.
Surprisingly, the Applicant has succeeded in synthesizing a hydrogel by reacting a macropolyol, in particular a hyperbranched polyglycerol, with a polyisocyanate, in particular a diisocyanate.
In particular, the Applicant has succeeded, in one aspect of the invention, in synthesizing a hydrogel by reacting a macropolyol, in particular a hyperbranched polyglycerol, with an isocyanate-terminated prepolymer and/or by direct reaction with a mixture of polyols and polyisocyanates.
Thus, a first object of the invention relates to a crosslinkable composition comprising:
A1) at least one multifunctional isocyanate-terminated urethane prepolymer comprising from 1 to 16 isocyanate functionalities on average, the average functionality being strictly greater than 1, the prepolymer being a product of the reaction of a diisocyanate, a triisocyanate, or a polyisocyanate of functionality strictly greater than 3, preferably aliphatic or cycloaliphatic and liquid at 25° C.±3° C., with a monofunctional polyol or alcohol comprising 1 to 8, preferably 2 to 3, hydroxyl groups; and/or
A2) at least one mono-, di- or polyisocyanate and/or oligoglycerol, and
A second object of the invention relates to a crosslinked composition capable of forming a hydrogel polymer by absorption of water, resulting from the crosslinking of a crosslinkable composition of the invention, either under anhydrous conditions or in the presence of small amounts of water, in particular so as to promote the formation of urea bonds, and either under an inert atmosphere or under an ambient atmosphere, for example according to a process for preparing a crosslinked composition according to the invention as described below.
“Crosslinkable composition”, in the sense of the present invention, means a composition which is liquid at room temperature and which can be converted to a material, in particular by reaction of its various constituents after bringing into contact by mixing, optionally adding catalysts and increasing the temperature.
The crosslinkable composition has the following characteristics:
“Prepolymer”, in the sense of the present invention, means an oligomer or a polymer having reactive groups which enable it to participate in a subsequent polymerization, and thus to incorporate several monomer units into at least one chain of the final macromolecule or into the final polymeric material constituting the hydrogel.
The prepolymer may be liquid at room temperature (i.e., about 25° C.±3° C.), or it may be solid at room temperature. The prepolymer is preferably liquid at the temperature at which the formation reaction is carried out.
The prepolymer of the present invention may be a multifunctional isocyanate-terminated urethane prepolymer comprising from 1 to 16 isocyanate functionalities. For example, it may be 0, 1, 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16 isocyanate functionalities. The average functionality is strictly greater than 1 for crosslinking and hydrogel network formation to occur. For example, the average functionality may be at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 7, or even greater than 7. Advantageously, in a mixture of isocyanates and polyisocyanates as described in the invention, molecules of functionality 2 must be present. The average functionality can be calculated as the molar average of the functionalities of the individual molecules.
Advantageously, the prepolymer can be a crosslinking agent.
The prepolymer is prepared separately, before mixing with the other components of the crosslinkable composition of the invention, by pre-reacting a polyisocyanate, for example a diisocyanate, triisocyanate or polyisocyanate of functionality strictly greater than 3, with a polyol, which may be linear or branched, comprising 1 to 8, preferably 2 to 6, hydroxyl groups.
The diisocyanate, triisocyanate and polyisocyanate with a functionality strictly greater than 3, hereinafter referred to as “polyisocyanate(s)”, may be aliphatic or cycloaliphatic. They are liquid at room temperature (about 25° C.±3° C.).
The triisocyanate can be, for example, aliphatic and without aromatic units. It can be, for example, functional trimer (isocyanurate) of isophorone diisocyanate, hexamethylene diisocyanate trimer.
The prepolymer can be derived from a polyisocyanate with a functionality greater than 2, for example an isocyanurate or an allophanate.
Whether used in the context of the prepolymer or as a constituent as such of the crosslinked and/or crosslinkable composition, the diisocyanate may be of the following formula: OCN—R1—NCO, wherein R1 represents a linear or branched, monocyclic or polycyclic or acyclic C1 to C15 alkylene, a C1 to C4 alkylidene, or a C6-C10 arylene optionally bearing at least one substituent selected from linear or branched C1-C6 alkyl, C1-C2 alkylene, or halogen atom. The diisocyanate may be selected from methylene dicyclohexyl diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, toluene-2,4-diisocyanate, toluene-2,6-diisocyanate, mixtures of toluene-2,4 and 2,6-diisocyanates, ethylene diisocyanate, ethylidene diisocyanate, propylene-1,2-diisocyanate, cyclohexylene-1,2-diisocyanate, cyclohexylene-1,4-diisocyanate, m-phenylene diisocyanate, 4,4′-biphenylene diisocyanate, 3,3′-dichloro-4,4′-biphenylene diisocyanate, 1,4-tetramethylene diisocyanate, 1,10-decamethylene diisocyanate, cumene-2,4 diisocyanate, 1,5-naphthalene diisocyanate, 1,4-cyclohexylene diisocyanate, 2,5-fluorenediisocyanate, 2,2′-diphenylmethylene diisocyanate, 4,4′-diphenylmethylene diisocyanate, 4,4′-dibenzyl diisocyanate, m-xylylene diisocyanate, hexamethylene diisocyanate trimer, and polymers of 4,4′-diphenylmethane diisocyanate, diphenyl-4,4″-biphenylene diisocyanate, 1,6-hexamethylene diisocyanate, m-phenylene diisocyanate, p-tetramethyl xylylene diisocyanate, p-phenylene diisocyanate, 4-methoxy-1,3-phenylene diisocyanate, 4-chloro-1,3-phenylene diisocyanate, 4-bromo-1,3-phenylene diisocyanate, 4-ethoxy-1,3-phenylene diisocyanate, 2,4-dimethyl-1,3-phenylene diisocyanate, 5,6-dimethyl-1,3-phenylene diisocyanate, 2,4-diisocyanatodiphenylether, 4,4″-diisocyanatodiphenylether, benzidine diisocyanate, 4,6-dimethyl-1,3-phenylene diisocyanate, 1,4-anthracene diisocyanate, 4,4′-diisocyanatodibenzyl, 3,3′-dimethyl-4,4′-diisocyanatodiphenylmethane, 2,6-dimethyl-4,4′-diisocyanatodibenzyl, 2,4-diisocyanatostilbene, 3,3′-dimethoxy-4,4′-diisocyanatodiphenyl, 2,5-fluorenediisocyanate, 1,8-naphthalene diisocyanate, 2,6-diisocyanatobenzofuran, xylene diisocyanate, m-tetramethyl xylylene diisocyanate or methylene diisocyanatodiphenyl. Preferably, it can be hexamethylene diisocyanate, isophorone diisocyanate or methylenebis(4-cyclohexyl)diisocyanate.
The polyol used in the context of the preparation of the prepolymer, also called polyalcohol monofunctional alcohol or glycol, can comprise from 1 to 8 hydroxyl groups, for example 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8 hydroxyl groups, preferably 2 to 3 hydroxyl groups. It can be selected from linear or branched poly(ethylene glycols) (PEG) or poly(propylene glycols) (PPG) comprising at least one hydroxyl function; molecular polyols comprising at least one hydroxyl function; co-polymers of poly(ethylene glycols) (PEG) and poly(propylene glycols) (PPG); and diols comprising silanes or polysiloxanes with terminal hydroxyl functions. The polyol may be particularly selected from ethylene glycol, diethylene glycol, triethylene glycol, trimethylolpropane, glycerol, pentaerythritol, xylitol, sorbitol, ethanol, butanol, phenol, 1,2-propylene glycol, dipropylene glycol, 1,4-butane diol, hexamethylene glycol, polydimethylsiloxanediols, and linear or branched PEG/PPG copolymers, such as the compounds in the Pluronic® or Tetronic® commercial ranges.
Advantageously, the PEGdiols and PPGdiols can have a molar mass comprised between 200 g/mol and 6000 g/mol, preferentially between 200 g/mol and 5000 g/mol. For example, the prepolymer obtained may be poly(ethylene glycol)-hexamethylene diisocyanate (i.e., a difunctional polyethylene glycol functionalized at each end with a hexamethylene diisocyanate, leading to a polyethylene glycol with two terminal isocyanate functions), poly(ethylene glycol)-isophorone diisocyanate (i.e., a difunctional polyethylene glycol functionalized at each end with isophorone diisocyanate, leading to a polyethylene glycol with two terminal isocyanate functions), methylenebis(4-cyclohexyl)isocyanate poly(ethylene glycol) diisocyanate (PEG-(h-MDI)2) (i.e., a difunctional polyethylene glycol functionalized at each end with methylenebis(4-cyclohexyl)isocyanate, leading to a polyethylene glycol with two terminal isocyanate functions), or trimethylene propane ethoxylate-triisocyanate hexamethylene diisocyanate (i.e., a trifunctional polyethylene glycol functionalized at each end with hexamethylene diisocyanate, leading to a polyethylene glycol with three terminal isocyanate functions). The reaction between the diisocyanate or triisocyanate and the polyol, allowing the formation of the prepolymer, can take place in a solvent medium, for example an aprotic polar solvent of the dimethylformamide, acetonitrile or dimethylsulfoxide type. Alternatively, the reaction can take place in bulk, i.e., without solvent. In solventless systems, the mixture between the prepolymer and the polyisocyanate is liquid at the processing temperature. For example, the prepolymer can be prepared at temperatures of about 60° C. in solventless systems, if necessary.
In the context of the preparation of the prepolymer, the isocyanate/hydroxyl stoichiometric ratios used can be between 2.2:1 and 1.1:1, for example 2:1, particularly in the case of reactions between diisocyanates and diols. The reaction temperatures can range from room temperature to 120° C., preferably between 25 and 80° C., more preferentially at 70° C., for example for 1 to 12 h until the prepolymer is formed, which can be characterized by 1H NMR, IR, SEC or by titration of the residual NCO groups.
In the context of the preparation of the prepolymer, the addition of a catalyst is optional, but may be carried out to accelerate the reaction rate. The catalyst may be selected from organobismuth, organometallic tin salts such as tin dibutyl laurate and/or tin octoate, iron tetrachloride, tertiary amines such as triethylamine, and mixtures thereof. The catalyst may be present in an amount of 0.01 to 2% by weight of the reactants, for example from 0.03 to 0.08% by weight of the prepolymer, preferably 0.05% by weight.
In the context of the preparation of the prepolymer, prior to the reaction with the polyisocyanate, the polyol can be dried under reduced pressure at a temperature comprised between 60 and 100° C., preferably between 70 and 90° C., for 12 to 24 hours to avoid the presence of moisture; indeed, the prepolymer formed is reactive in the presence of water, so it is preferable to dry the multifunctional compounds and the polyols/diols before proceeding with the mixing. It can then be introduced as is into the reaction medium if the reaction takes place in bulk, or as a solution if the reaction takes place in solvent under inert atmosphere (argon/nitrogen). The polyisocyanate used can be taken under an inert gas (nitrogen/argon) flow and added as is to the reaction medium if the reaction takes place in bulk, or as a solution if the reaction takes place in solvent, for example under stirring between 25° C. (ambient temperature) and 120° C., advantageously between 40 and 90° C., such as for example at 70° C. The reaction product can be recovered hot under inert gas (argon/nitrogen) flow and stored cold, for example at temperatures close to zero, or down to 5° C.
When at least one monoisocyanate is used as a constituent of the composition as such, apart from that incorporated in the prepolymer, it can advantageously have a chain-limiting role for modulus modulation. This can be any monoisocyanate suitable for the reaction conditions, in particular liquid aliphatic or aromatic isocyanates, such as butyl isocyanate.
When at least one diisocyanate is used as a constituent of the composition as such, apart from that incorporated in the prepolymer, it may be aromatic, aliphatic or cycloaliphatic, preferably aliphatic or cycloaliphatic. The diisocyanate may have the following formula: OCN—R1—NCO, wherein R1 is a linear or branched, monocyclic or polycyclic or acyclic C1 to C15 alkylene, a C1 to C4 alkylidene, or a C6-C10 arylene optionally bearing at least one substituent selected from linear or branched C1-C6 alkyl, C1-C2 alkylene, or a halogen atom. When a polyisocyanate is used as a constituent as such, it may have an average functionality greater than or equal to 2, for example 3 or 4. Preferably, the di- or polyisocyanate is aliphatic and free of aromatic units, and liquid at room temperature (i.e., about 25° C.). The di- or polyisocyanate is used in an amount between 1 and 60% by weight, for example between 5 and 50% by weight. In any event, the amount of di- or polyisocyanate can be adjusted, according to the general knowledge of the person skilled in the art, and in light of the present invention, to modify the properties of the hydrogel of the invention. The di- and polyisocyanates may be selected from methylene dicyclohexyl diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, toluene-2,4-diisocyanate, toluene-2,6-diisocyanate, mixtures of toluene 2,4 and 2,6-diisocyanates, ethylene diisocyanate, ethylidene diisocyanate, propylene-1,2-diisocyanate, cyclohexylene-1,2-diisocyanate, cyclohexylene-1,4-diisocyanate, m-phenylene diisocyanate, 4,4′-biphenylene diisocyanate, 3,3′-dichloro-4,4′-biphenylene diisocyanate, 1,4-tetramethylene diisocyanate, 1,10-decamethylene diisocyanate, cumene-2,4 diisocyanate, 1,5-naphthalene diisocyanate, 1,4-cyclohexylene diisocyanate, 2,5-fluorenediisocyanate, 2,2′-diphenylmethylene diisocyanate, 4,4′-diphenylmethylene diisocyanate, 4,4′-dibenzyl diisocyanate, m-xylylene diisocyanate, hexamethylene diisocyanate trimer, methylene dicyclohexyl diisocyanate, biphenylene diisocyanate, 1,6-hexamethylene diisocyanate, m-phenylene diisocyanate, 1,4-tetramethylene diisocyanate, polymers of 4,4′-diphenylmethane diisocyanate, p-tetramethyl xylylene diisocyanate, p-phenylene diisocyanate, 4-methoxy-1,3-phenylene diisocyanate, 4-chloro-1,3-phenylene diisocyanate, 4-bromo-1,3-phenylene diisocyanate, 4-ethoxy-1,3-phenylene diisocyanate, 2,4-dimethyl-1,3-phenylene diisocyanate, 5,6-dimethyl-1,3-phenylene diisocyanate, 2,4-diisocyanatodiphenylether, 4,4″-diisocyanatodiphenylether, benzidine diisocyanate, 4,6-dimethyl-1,3-phenylene diisocyanate, 1,4-anthracene diisocyanate, 4,4′-diisocyanatodibenzyl diisocyanate, 3,3′-dimethyl-4,4′-diisocyanatodiphenylmethane, 2,6-dimethyl-4,4′-diisocyanatodibenzyl, 2,4-diisocyanatostilbene, 3,3′-dimethoxy-4,4′-diisocyanatodiphenyl, 2,5-fluorenediisocyanate, 1,8-naphthalene diisocyanate, 2,6-diisocyanatobenzofuran, xylene diisocyanate, m-tetramethyl xylylene diisocyanate; preferably hexamethylene diisocyanate, isophorone diisocyanate and methylenebis(4-cyclohexyl)diisocyanate or a polyisocyanate with a functionality greater than 2, for example the trifunctional trimer (isocyanurate) of isophorone diisocyanate or the trifunctional (isocyanurate) trimers of hexamethylene diisocyanate and 4,4-diphenyl methane diisocyanate polymer, as well as the corresponding allophanates, biurets or uretdiones.
Advantageously, the macropolyol used in the invention has a crosslinking role.
“Oligoglycerol”, in the sense of the present invention, means a glycerol polymer, the average degree of polymerization of which is less than or equal to 7, for example from 2 to 7. The degree of polymerization and the average degree of polymerization can be determined by any method known to the person skilled in the art, for example by size-exclusion chromatography and 1H and 13C NMR. The oligoglycerol may be functionalized. The oligoglycerol may be linear, branched or hyperbranched. Oligoglycerols are commercially available, for example diglycerol (INCI Diglycerin), polyglycerol-3 (Polyglycerin-3) and polyglycerol-4 (Polyglycerin-4), distributed by the company Inovyn.
“Glycerol dendrimer”, in the sense of the present invention, means a molecule consisting of 1 or more dendrons emanating from a single constituent unit, a dendron being a molecule having a single free valence or focal unit, comprising exclusively constituent repeating units of a dendritic and terminal nature, wherein each path from the free valence (focal unit) to any of the terminal units comprises the same number of constituent repeating units. The molar mass of a dendrimer may be comprised between 500 and 100 000 g/mol, for example between 500 and 6000 g/mol, or between 800 and 4000 g/mol, having degrees of polymerization (DP) comprised between 5 and 70; dispersities between 1 and 1.8 and degrees of branching (DB) comprised between 0.9 and 1, optionally prepared as described in the paper J. Am. Chem. Soc. 2000, 122, 2954-2955 ([3]).
“Polyglycerol”, in the sense of the invention, means a glycerol polymer consisting of glycerol units linked by ether bonds, the molar mass of which may be between 500 (DP=7) and 100 000 (DP=1350) g/mol (500 may be excluded or included), for example between 500 and 10 000 g/mol, or between 800 and 6000 g/mol. The polyglycerol may have dispersities between 1.1 and 5, for example between 1.1 and 1.8. It can be, for example, linear, branched or hyperbranched polyglycerols. “Linear” oligoglycerol or polyglycerol, in the sense of the present invention, means a glycerol polymer comprising a chain of glycerol units linked together by ether bonds established essentially between the primary alcohol functions of the glycerol.
“Branched” polyglycerol or oligoglycerol, in the sense of the invention, means a glycerol polymer having a branched three-dimensional structure, which may have a DB (Degree of Branching, as defined by Frey, namely DB=(2D/(2D+L)) comprised between 0.05 and 0.3 (Nomenclature and Terminology for Dendrimers with Regular Dendrons and for Hyperbranched Polymers A. Fradet, J. Kahovec, IUPAC Nomenclature Project Nr: 2001-081-1-800 ([2])). In general, the degree of branching (DB) can be determined using classical state of the art methods, for example by inverse-gated 13C NMR.
“Hyperbranched” polyglycerol or oligoglycerol, in the sense of the present invention, means a substance composed of hyperbranched macromolecules which consist of chains joined by a common core and a substantial fraction of branched glycerol repeating units and glycerol terminal units but also comprising linear glycerol repeating units such that the degree of branching DB defined by H. Frey is comprised between 0.3 and 0.8, more frequently between 0.3 and 0.7 (A. Fradet and J. Kahovec ([2])).
As mentioned above, the hyperbranched polyglycerol, optionally functionalized, may have a molar mass comprised between 500 and 100 000 g/mol, preferably between 500 and 10 000 g/mol, and may have degrees of polymerization (DP) between 7 and 1350, dispersities between 1.1 and 5, for example between 1.1 and 1.8, and degrees of branching (DB) between 0.3 and 0.7. Polyglycerols with degrees of branching equal to 1 can be used and prepared, for example, according to the method described in the paper J. Am. Chem. Soc. 2000, 122, 2954-2955 ([3]).
Alternatively, the glycerol polymer may be a mixture of hyperbranched polyglycerols and linear, branched or hyperbranched oligoglycerols, for example with a degree of polymerization comprised between 2 and 7, optionally functionalized. In the mixture, the ratio of hyperbranched polyglycerols to linear, branched or hyperbranched oligoglycerols is from 100:0 to 80:20 by weight.
The macropolyol can be obtained by any method known to the skilled person, for example by ring-opening polymerization of glycidol or glycerol carbonate, using one or more mono- or polyfunctional initiators such as, for example, monoalcohols like methanol, butanol, phenol and derivatives thereof, benzyl alcohol, 1-dodecanol, 1-tetradecanol, 1-hexadecanol, glycol monoalkylethers such as glycol monoethyl ethers or polyethylene glycol monoalkylethers, such as for example polyethylene glycol monoethyl ether, diols such as ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycols, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,5-pentanediol, 2,3-pentanediol, 2,4-pentanediol, 1,2-hexanediol, 1,3-hexanediol, 1,4-hexanediol, 1,5-hexanediol, 1,6-hexanediol, 2,5-hexanediol, 1,2-heptanediol, 1,7-heptanediol, 1,8-octanediol, 1,2-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,2-decanediol, 1,12-dodecanediol, 1,2-dodecanediol, 1,5-hexadiene-3,4-diol, cyclopentanediols, cyclohexanediols, inositol and derivatives thereof, (2)-methyl-2,4-pentanediol, 2,4-dimethyl-2,4-pentanediol, 2-ethyl-1,3-hexanediol, 2,5-dimethyl-2,5-hexanediol, 2,2,4-trimethyl-1,3-pentanediol, pinacol, dipropylene glycol, polypropylene glycols, 1,4-butanediol, hexamethylene glycol, bisphenol A, bisphenol F, bisphenol S, diethylene glycol, triethylene glycol, dipropylene glycol, tripropylene glycol, polyethylene glycols HO(CH2CH2O)n-H or polypropylene glycols HO(CH[CH3]CH2O)n—H (where n is an integer greater than or equal to 4) or mixtures of two or more of the above compounds. It is also possible to use triols or polyols with a functionality greater than 3 such as glycerol, diglycerol, triglycerol, tetraglycerol, trimethylolethane, trimethylolpropane, di-trimethylolpropane, sorbitol, but also hydroxyl-terminated oligomers such as ethoxylated pentaerythritols and propoxylated pentaerythritols, ethoxylated trimethylolpropanes and propoxylated trimethylolpropanes, ethoxylated or propoxylated glycerols, resulting from the ring-opening addition reaction of ethylene oxide and/or propylene oxide to pentaerythritol, trimethylolpropane and glycerol. The degree of ethoxylation is typically comprised between 0.1 and 10 ethylene oxide units per OH function. The molar mass is generally comprised between 100 and 1000 g/mol. Ethoxylated trimethylolpropanes, ethoxylated glycerols and ethoxylated pentaerythritols may be preferentially used. “Star” molecules with at least three arms comprising polyoxypropylene-polyoxyethylene blocks can also be used such as ethoxylated or propoxylated sorbitols and saccharides, degraded starch, polyvinyl alcohol. It is also possible to use initiators such as water, methylamine, ethylamine, propylamine, butylamine, dodecylamine, myristylamine, palmitylamine, stearylamine, aniline, benzylamine, ortho- or para-toluidine, α,β-naphthylamine, ammonia, ethylene diamine, propylene diamine, 1,4-butylene diamine, 1,2-, 1,3-, 1,4-, 1,5-, or 1,6-hexamethylene diamines, as well as o-, m- and p-phenylene diamines, 2,4- and 2,6-tolylenediamine, 2,2′-, 2,4 and 4,4′-diaminodiphenylmethane, 2,2′-, 2,4 and 4,4′-diaminodicyclohexylmethane, diethylene glycol diamine, diethylene triamine, triethylene tetramine, difunctional or trifunctional poly(propylene glycol)diamines (Jeffamines). Amino alcohols such as diethanolamine, dipropanolamine, diisopropanolamine, triethanolamine, tris(hydroxymethyl)aminomethane or diisopropylethanolamine can also be used, but also compounds containing functional groups such as allyl alcohol, allylglycerol, 10-undecenol, 10-undecenamine, or dibenzylamine.
The initiator used in the context of the preparation of the macropolyol can then be partially deprotonated with a suitable agent selected from alkali metals and their hydrides, alkoxides, hydroxides. Preferentially, metals or metal alkoxides such as potassium methanolate (MeOK) are used. Potassium carbonate can also be used as a catalyst for the polymerization of glycerol carbonate in particular.
Other molecules can be used to catalyze the polymerization to obtain the macropolyol, such as alcoholates, organometallic compounds, metal salts, tertiary amines. Among the alcoholates, alkali metal alcoholates such as sodium methylate, potassium isopropylate or potassium methanolate can be used. It is also possible to use tetraalkylammonium hydroxides, such as tetramethylammonium hydroxides; alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; metal salts, such as organic and/or inorganic compounds based on iron, lead, bismuth, zinc and/or tin at conventional metal oxidation levels, for example: iron(II) chloride, iron(III) chloride, bismuth(III) 2-ethylhexanoate, bismuth(III) octoate, bismuth(III) neodecanoate, zinc chloride, zinc 2-ethylcaproate, tin(II) octoate, tin(II) ethylcaproate, tin(II) palmitate, tin(IV) dibutyldilaurate (DBTL), tin(IV) dibutyldichloride or lead octaote or amidines, such as 2,3-dimethyl-3,4,5,6-tetrahydropyrimidine. It is also possible to use alkali metal salts of long-chain fatty acids having 10 to 20 carbon atoms and optionally pendant OH groups. It is also possible to use tertiary amines such as triethylamine, tributylamine, dimethylbenzylamine, diethylbenzylamine, pyridine, methylpyridine, dicyclohexylmethylamine, dimethylcyclohexylamine, N,N,N′,N′-tetramethyldiaminodiethyl ether, bis(dimethylaminopropyl)-urea, N-methyl- and N-ethylmorpholine, N-cocomorpholine, N-cyclohexylmorpholine, N,N,N′,N′-tetramethylethylenediamine, N,N,N′,N′-tetramethyl-1,3-butanediamine, N,N,N′,N′-tetramethyl-1,6-hexanediamine, pentamethyldiethylenetriamine, N-methylpiperidine, N-dimethylaminoethylpiperidine, N, N′-dimethylpiperazine, N-methyl-N′-dimethylaminopiperazine, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene), 1,2-dimethylimidazole, 2-methylimidazole, N, N-dimethylimidazole, 3-phenylethylamine, DABCO or 1,4-diazabicyclo-(2,2,2)octane, bis-(N,N-dimethylaminoethyl)adipate; alkanolamine-type compounds, such as triethanolamine, triisopropanolamine, N-methyl- and N-ethyl-diethanolamine, dimethylaminoethanol, 2-(N, N-dimethylaminoethoxy)ethanol, N,N′, N″ tris-(dialkylaminoalkyl)hexahydrotriazines, such as N, N′, N″ tris-(dimethylaminopropyl)-s-hexahydrotriazine and/or (dimethylaminoethyl)ether.
The macropolyol synthesis reaction can take place in the presence of solvent, for example an aliphatic, cycloaliphatic or aromatic solvent such as decalin, toluene or xylene, or an ether such as glyme, diglyme or triglyme. Alternatively, the reaction can take place in bulk, for example between 40 and 140° C., preferably at 95° C. in semi-batch, advantageously corresponding to a slow and controlled addition of the glycidol monomer and optionally of its co-monomers to the reaction medium.
The macropolyol can also be obtained by co-polymerization with other functionalized monomers which can incorporate at least one group selected from fluorinated, silane, siloxane and halogenated compounds such as propylene oxide, ethylene oxide, butylene oxide, epichlorohydrin, vinyloxirane, glycidyl allyl ether, glycidyl methacrylate, isopropyl glycidyl ether, phenyl glycidyl ether, 2-ethylhexyl glycidyl ether, hexadecyl glycidyl ether, naphthyl glycidyl ether, t-butyldimethylsilyl-(R)-(−)-glycidyl ether, benzyl glycidyl ether, epoxy-3-phenoxypropane, biphenyl glycidyl ether, propargyl glycidyl ether, n-alkyl glycidyl ethers, but also functionalized oxiranes such as γ-glycidylpropyltrimethoxysilane, γ-glycidylpropyltriethoxysilane γ-glycidoxypropyl-bis(trimethylsiloxy)-methylsilane and 3-(bis(trimethylsiloxy)methyl)-propyl glycidyl ether, glycidylglycerol ether, glycidyl butylether, glycidylnonylphenylether, fluorinated and perfluorinated oxiranes such as hexafluoropropylene oxide, 2,3-difluoro-2,3-bis-trifluoromethyl-oxirane, 2,2,3-trifluoro-3-pentafluoroethyl-oxirane, 2,3-difluoro-2-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-3-trifluoromethyl-oxirane, 2-fluoro-2-pentafluoroethyl-3,3-bis-trifluoromethyl-oxirane, 1,2,2,3,3,4,4,5,5,6-decafluoro-7-oxa-bicyclo[4.1.0]heptane, 2,3-difluoro-2-trifluoromethyl-3-pentafluoroethyl-oxirane, 2,3-difluoro-2-nonafluorobutyl-3-trifluoromethyl-oxirane, 2,3-difluoro-2-heptafluoropropyl-3-pentafluoroethyl-oxirane, 2-fluoro-3-pentafluoroethyl-2,3-bis-trifluoromethyl-oxirane, 2,3-bis-pentafluoroethyl-2,3-bistrifluoromethyl-oxirane, 2,3-bis-trifluoromethyl-oxirane, 2-pentafluoroethyl-3-trifluoromethyl-oxirane, 2-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-3-trifluoromethyl-oxirane, 2-nonafluorobutyl-3-pentafluoroethyl-oxirane, 2,2-bis-trifluoromethyl-oxirane 2-heptafluoroisopropyloxirane, 2-heptafluoropropyloxirane, 2-nonafluorobutyloxirane, 2-tridecafluorohexyloxirane, and HFP (hexafluoropropene) trimer oxiranes including 2-pentafluoroethyl-2-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-3,3-bis-trifluoromethyl-oxirane, 2-fluoro-3,3-bis-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-2-trifluoromethyl-oxirane, 2-fluoro-3-heptafluoropropyl-2-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-3-trifluoromethyl-oxirane and 2-(1,2,2,3,3,3-hexafluoro-1-trifluoromethyl-propyl)-2,3,3-tris-trifluoromethyl-oxirane. These types of compounds or moieties can be introduced in situ by copolymerization or by post-modification.
The crosslinkable composition may comprise, in addition to the polyol used in the preparation of the prepolymer, optionally at least one polyol, for example 1, or 2, or 3, or 4 polyols, wherein the polyol may preferably comprise at least two hydroxyl groups. Advantageously, the polyol may serve as a chain extender or co-crosslinker.
The polyol may be of the di- or multifunctional poly(ethylene glycol) (PEG) or poly(propylene glycol) (PPG) type, depending on the type of initiator used. In particular, it can be prepared by ring-opening polymerization of ethylene oxide and/or propylene oxide from a polyol or a monofunctional alcohol selected from ethylene glycol, diethylene glycol, triethylene glycol, trimethylolpropane, glycerol, pentaerythritol, xylitol, sorbitol, ethanol, butanol, phenol, 1,2-propylene glycol, dipropylene glycol, 1,4-butane diol and hexamethylene glycol.
The monofunctional polyols or alcohols may alternatively be molecular polyols of the type ethylene glycol, diethylene glycol, triethylene glycol, trimethylolpropane, glycerol, pentaerythritol, xylitol, sorbitol, ethanol, butanol, phenol, 1,2-propylene glycol, dipropylene glycol, polypropylene glycol, 1,4-butane diol, or hexamethylene glycol. The polyol can be obtained by any method known to the skilled person, for example by using one or more mono- or polyfunctional initiators such as those indicated above for the macropolyol.
The polyol can alternatively be a diol incorporating silane or siloxane groups such as hydroxyl-terminated dihydroxytelechelic polydimethylsiloxane, but also diblock or triblock block copolymers of polydimethylsiloxane and polycaprolactone, of polydimethylsiloxane and polyoxyethylene or of polydimethylsiloxane and polypropylene glycol.
The polyols used can alternatively be linear or branched copolymers, for example based on PEG/PPG such as Pluronic® or Tetronic®. Advantageously, the copolymers can be as described in the document EP2496620 ([1]).
The composition of the invention may optionally comprise at least one monofunctional alcohol, a mixture of monofunctional alcohols or a monohydroxylated polyether based on ethylene glycol and/or ethylene glycol/propylene glycol, or a mixture of monohydroxylated polyether and monofunctional alcohols. It may be at least one, for example 2, or 3, or 4, monohydroxy polyethers or monofunctional alcohols, preferably 1 or 2. “Ethylene glycol and/or ethylene glycol/propylene glycol based” means a polyether essentially consisting of ethylene glycol monomer units. Advantageously, they can be used to limit and/or control the crosslinking rate, and thus control the density of the network, and consequently all the properties ranging from mechanical properties to maximum water contents, etc. They can be included in the composition of the invention in an amount of 0 to 20% by weight.
The composition of the invention may optionally comprise at least one catalyst or combination of catalysts. Advantageously, the catalyst may be capable of catalyzing the polymerization or accelerating the reaction rate. The catalyst may be selected from bismuth, tin, titanium or organobismuth based organometallics, for example bismuth(III) tricarboxylates, bismuth-2-ethylhexanoate, bismuth neodecanoate, tin dibutyl laurate, tin octoate (Sn(oct)2), and/or an orthotitanate such as tetra-n-butylorthotitanate, iron tetrachloride, tertiary amines such as triethylamine, tributylamine or any other commonly used trialkylamine as well as nucleophilic molecules such as 1,4-diazabicyclo[2.2.2]octane (DABCO), triazabicyclodecene (TBD), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
The composition of the invention may optionally comprise at least one additive for example selected from:
The at least one additive may represent between 0 and 20% of the total mass of the composition of the invention. For example, it may be between 1 and 18%, or between 2 and 15%, or between 5 and 10% of the total mass of the composition of the invention.
When the crosslinked or crosslinkable composition comprises an agent selected from UV filters, UV absorbers and blue-light filters, it may be, for example, any commercially available UV filter, such as AEHB (acryloxyethoxyhydroxybenzophenone), and/or any UV absorber having high absorption in the UV-A range (320-380 nm) but relatively transparent above 380 nm. Generally, if the UV absorber is present in the composition of the invention, it is present between 0.5 and 1.5% by weight of the reactants, for example at 1% by weight. The UV absorbers can be incorporated into the hydrogel at the post-polymerization hydration step.
Advantageously, the crosslinkable or crosslinked composition of the invention may comprise, as a percentage by weight based on the total weight of the composition:
Advantageously, the crosslinked composition of the invention comprises:
Another object of the invention relates to a hydrogel obtainable by water absorption/water swelling of a crosslinked composition according to the invention, or, when an aprotic solvent is present in the crosslinked composition, by exchange of the aprotic solvent with excess water.
Hydrogels contain, after hydration, a certain amount of water, which can be determined by means of successive mass measurements after hydration (for example after 12 h, with distilled water or solutions having the physicochemical characteristics of tear fluid) and after drying (for example for 12 h, at 90° C.). The water content (EWC, in %) can be expressed according to equation 1 below:
With w representing the mass in the hydrated state, and wo the mass in the “dehydrated” or dry state.
Similarly, a swelling ratio (SR, in %) can be determined according to equation 2 below
Advantageously, the hydrogel has a theoretical permeability allowing the applications mentioned below. According to the previously determined water content and according to the equation of Fatt & Chaston (3), a theoretical permeability (Dk) in Barrer of the hydrogel can be estimated:
Dk=2.0×10−11xe0.0411 EWC (3)
The mechanical properties of the hydrogel, including Young's modulus, stress at break, and elongation at break, can be determined by any method known to the skilled person, for example, by means of a tensile machine. Preferably, the tested samples are all of similar dimensions (for example, 3 mm wide by 1 cm long), and the thickness can be measured with each new analysis. The analysis can be started with a preload of 0.1 N at a strain rate equivalent to 20 mm/min.
The surface properties of the designed materials can also be analyzed via various techniques known to the skilled person, such as optical microscopy, atomic force microscopy, wettability, coefficient of friction and surface roughness measurements.
Another object of the invention relates to a process for preparing a crosslinked composition according to the invention, consisting of reacting, in the presence or absence of aprotic solvent, preferably in the absence of solvent:
A1) at least one urethane prepolymer as defined above, with a polyol or a monofunctional alcohol comprising 1 to 8, preferably 2 to 3, hydroxyl groups; and/or
A2) at least one di- or polyisocyanate and/or oligoglycerol;
with
B) at least one macropolyol as defined above;
and:
C) optionally at least one polyol as defined above;
D) optionally at least one monoalcohol, a mixture of monoalcohols or a monohydric polyether based on ethylene glycol and/or ethylene glycol/propylene glycol, or a mixture of monohydric polyether and monoalcohols as defined above;
E) optionally at least one catalyst or combination of catalysts as defined above;
F) optionally at least one additive as defined above; and
G) optionally at least one agent selected from UV filters, UV absorbers and blue-light filters as defined above.
The aprotic solvent, when used, is selected from polar aprotic solvents such as dimethylformamide, acetonitrile, dimethylacetamide and dimethylsulfoxide, or a mixture of at least two of these.
The process of the invention can be carried out under ambient conditions and/or under anhydrous conditions and under inert atmosphere. In the sense of the present invention, “atmosphere and ambient conditions” means non-anhydrous conditions, a non-inert atmosphere, at about 25° C. (±3° C.). The ingredients must be liquid either because of a higher temperature if necessary, obtained for example by heating, or because of the presence of solvent, or because of the use of low molar mass compounds. These low molar mass compounds can be diisocyanates which can liquefy solid prepolymers, and/or polyols with a degree of polymerization less than or equal to 7, for example glycols to liquefy potentially solid high molar mass polyols and macropolyols. Therefore, the temperature of the process of the invention can be comprised between 10° C. and 90° C., preferentially between 25° C. and 80° C.
The duration of the process of the invention can be such as to allow the total consumption of the isocyanate functions, either by reaction with the hydroxyl functions of the polyols and macropolyols when the reaction is carried out in anhydrous medium, or with the hydroxyl functions of the polyols, macropolyols and water if the reaction is carried out in the presence of water in limited and controlled amounts.
The various components used in the context of the process of the invention can be produced by means known to the skilled person, for example by mixing with a spatula, using a mechanical stirrer, or any mixers used by the skilled person for multi-component thermosetting formulations, such as, for example, with a speed mixer, with a two-component static mixer or using ultrasound.
Advantageously, the reaction mixture is relatively anhydrous, i.e., it contains little or no water, and in any case not as reactants. Indeed, to avoid an increase in modulus, which is undesirable in the case of materials used for the lens industry, the absence of urea groups or bonds in the gel composition is an advantage.
Alternatively, the reaction mixture may contain a controlled amount of water. Advantageously, this embodiment can control certain properties, such as improved water retention or modulus. At the end of the mixing step, the resulting mixture can be reacted under an inert atmosphere to form a three-dimensional crosslinked polyurethane network, which can be molded by various methods known to the skilled person. Advantageously, the step of molding the composition during the crosslinking can provide the composition with the desired shape. These methods can be, for example, spin-casting, or cast-molding. The molding step can take place under an inert atmosphere, in particular under an oxygen/nitrogen atmosphere, or under a controlled humidity atmosphere, i.e., either under an inert and therefore dry atmosphere, or under controlled humidity leading to the controlled formation of urea functions. This step can be carried out, for example, at a temperature comprised between 10 and 140° C., preferably between room temperature (i.e., about 25° C.) and 90° C., preferentially between 40 and 80° C.
The films, once in the molds, are placed in an oven at 40 to 100° C., preferably at 50 to 80° C. for 1 to 20 h, preferably 4 to 10 h, for example 8 h.
An annealing can also be applied, between 60 and 150° C., preferably between 70 and 100° C., for 2 min to 2 h, for example 20 min to 1 h. The characterization of the network by IR analysis can confirm the complete disappearance of isocyanate groups in the medium.
The process may further comprise a step of hydrating/swelling the crosslinked composition with excess water, to form a hydrogel. Alternatively, when an aprotic solvent is used, the process may further comprise a step of exchanging the aprotic solvent with excess water, advantageously to replace the aprotic solvent used in the preparation of the mixtures.
The process may further comprise a step selected from molding, lathe cutting, casting, two-component mixing, and speed mixing.
Another object of the invention relates to an article obtainable by a process for preparing a crosslinked composition according to the invention as defined above. The article may be a medical device, such as a contact or intraocular lens, a patch, a dressing or a medical implant for tissue engineering and/or delivery of active ingredients, or a superabsorbent material.
Another object of the invention relates to the use of a composition or hydrogel according to the invention for the manufacture of a medical device, such as a contact or intraocular lens, a patch, a dressing or a medical implant for tissue engineering and/or delivery of active ingredients, or a superabsorbent material.
Another object of the invention relates to the use of a composition or hydrogel according to the invention as a carrier for a compound of interest selected from therapeutic active ingredients, vitamins, nutrients, decontaminating agents or lubricants.
Among the active therapeutic ingredients or “therapeutic agents”, mention may be made of anti-inflammatory drugs, for example non-steroidal anti-inflammatory drugs (NSAIDs) or corticoids, antibiotics, alone or in combination, anti-glaucoma drugs, alone or in combination, anti-allergic drugs, alone or in combination, drugs for the treatment of the progression of myopia such as, for example, anticholinergic drugs, drugs for the treatment of presbyopia, and, more generally, treatments of ocular pathologies including the eye in its entirety and its appendages: eyelids, oculomotor muscle, lacrimal glands and their secretions, and orbits.
Non-drug substances may include vitamins and nutrients such as antioxidants, protective agents for the metabolism of the eye and its appendages, and lens decontaminants such as bacterial anti-biofilms, antifungals, antiamebics and antivirals.
The substances can be introduced after polymerization or before.
Another object of the invention relates to the use of a crosslinked composition as defined above, capable of forming a hydrogel polymer by swelling in the presence of a necessary and sufficient amount of water, for the manufacture of a medical device, such as a contact or intraocular lens, a patch, a dressing or a medical implant for tissue engineering and/or delivery of active ingredients and/or surgery. The crosslinked composition also has applications in the so-called “domestic” fields, for example as a perfume diffuser, in cosmetics, in the field of diapers, and in fields relating to the preservation of the environment, as for example with depollutants.
For example, the crosslinked composition can be derived from the reaction in the presence or absence of an aprotic solvent, under anhydrous conditions and under inert atmosphere, or under ambient atmosphere and conditions:
(a) of at least either an oligoglycerol, a dendrimer, an optionally functionalized linear, branched or hyperbranched polyglycerol, comprising at least 8 hydroxyl groups with at least one di- or polyisocyanate; optionally in the presence of at least one catalyst and/or optionally at least one additive selected from antioxidants, oxygen permeability promoters, plasticizers, humectants, lubricants, viscosity modifiers, compatibilizing agents, coloring agents, opacifying agents, antimicrobial agents, modulus modifiers, therapeutic agents and bacterial anti-biofilm agents; and/or optionally at least one agent selected from UV filters, UV absorbers and blue-light filters; or
(b) at least either an oligoglycerol, a dendrimer, a linear, branched or hyperbranched polyglycerol, optionally functionalized, comprising at least 10 hydroxyl groups, with at least one di- or polyisocyanate, and at least one polyol comprising 2 to 6, preferably 2 to 3, hydroxyl groups; optionally in the presence of at least one catalyst and/or optionally at least one additive selected from antioxidants, modulus modifiers, oxygen permeability modulators, plasticizers, humectants, lubricants, viscosity modifiers, compatibilizing agents, coloring agents, opacifying agents, antimicrobial agents, therapeutic agents, and bacterial anti-biofilm agents; and/or optionally at least one agent selected from UV filters, UV absorbers, and blue-light filters.
Other advantages may become apparent to the skilled person upon reading the examples below.
Determination of Oxygen Permeability (Dk) by Polarography
The polarographic method is based on a classical electrochemical setup with 3 electrodes: gold working electrode (WE), platinum counter electrode (CE) and Ag/AgCl reference electrode (RE), immersed in a 0.1 M electrolyte solution (KCl). The hydrogel is placed on the surface of the working electrode, then oxygen is injected into the electrochemical cell and the current variation is measured (oxidation of the oxygen on the surface of the WE). The intensity of the current measured will depend on the amount of oxygen passed through the hydrogel.
Three tests are performed for each sample, and the average of the three analyses is retained.
The potentiostat used for these analyses is a DropSens pSTAT 400.
Using a tensile testing machine (M500-30AT) equipped with a DBBMTCL 50 kg test cell, the mechanical properties determined are: Young's modulus, stress at break and elongation at break.
The dimensions of the hydrated samples are normalized to 3 mm width for 10 mm between the jaws, the thickness is measured at each new analysis. The preload is 0.1 N for a deformation rate equivalent to 20 mm/min all at room temperature. All specimens were evaluated at least 3 times and averages of the data calculated by the WinTest software were calculated.
The designed materials are also analyzed via different techniques including wettability measurements (a), surface roughness by atomic force microscopy (AFM) (b), friction coefficients by tribometer (c)
(a) Wettability Measurements
Surface properties were also determined by measurements of water contact angles on the materials using the drop-on-solid mode on a KRUSS DSA 100 apparatus. Briefly, a drop (2 μL) of distilled water is deposited on the material surface and the angle (in°) at equilibrium of the drop with the material is measured via a video camera. An average of 10 measurements is taken via DropShapeAnalysis software.
(b) Surface Roughness Measurements by Atomic Force Microscopy (AFM)
AFM analyses were performed on a Bruker Dimension EDGE instrument. The analyses were performed in Tapping mode. Levers of force 3 N/m with Si3N4 tips (Bruker, Product code: RFESP) were used to generate the phase, amplitude and height images. The height images allowed us to access the R(max), Ra and Rq, defined respectively as the maximum height identified on the sample surface; the average surface roughness and the standard deviation of the average flat surface. Samples were scanned at lengths of 20, 10, 5 and 1 μm to generate scanned areas of 400, 100, 25 and 1 μm2. Data were processed with Nanoscope Analysis software and compared with commercial lenses.
(c) Measurement of Friction Coefficients with a Tribometer
The measurements were performed on a CSM instrument tribometer. A steel ball of 10 mm diameter was used at a speed of 1 cm/sec, with a normal force of 0.5 N. 3 analyses were performed on each sample and an average of the 3 was calculated. The sample is in film form, and the analysis takes place in liquid medium (water or saline) at room temperature.
Transmittance was determined using a UV spectrophotometer. A lens is placed in a cell containing a saline solution. The cell is placed in the sample compartment. A cell containing only saline solution is placed in the reference compartment.
And the spectrum in % transmittance is recorded between 200 and 780 nm. The sample is analyzed 3 times and an average of the 3 measurements at 550 nm was retained.
The water content and swelling rate are determined by measuring the weight of the gel in the dry and hydrated state using Equations 1 and 2.
The gels in the hydrated state are weighed individually after removing excess water from the surface. The gels are then dried in an oven at 80° C. for a minimum of 6 h and weighed again. This process is repeated 3 times, and the EWC value is the average of the 3.
In a 250 mL three-necked flask, trimethylolpropane (TMP; 1 eq, 1.17 g, 8.7×10−3 mol) and 25% potassium methanolate in methanol (MeOK; 0.3 eq, 0.72 g, 2.6×10−3 mol) are introduced.
The flask is then placed in the rotary evaporator at 70° C. until complete dissolution of the TMP, then the rotary evaporator is put under vacuum to remove the methanol.
The three-necked flask containing the reagents is then placed in an oil bath thermostated at 95° C., topped by a stirring paddle (300 rpm) under nitrogen flow. Once the reaction medium is at temperature, glycidol (80 eq, 50 g, 0.675 mol) is added with a peristaltic addition pump at a rate of 3.6 m L/h.
Once the addition of glycidol is completed, the reaction medium is left under stirring for a few hours before being stopped. The obtained polymer is dissolved in methanol, deionized with Amberlite® and then precipitated twice in acetone.
The obtained macropolyol is characterized by size-exclusion chromatography (SEC) and 1H NMR spectroscopy
δ (ppm), MeOD: 4.92 (OH); 3.56 (CH2—CH2—O)n-2; 1.36 (CH2, TMP); 0.87 (CH3, TMP)
The same protocol as that of Example 1 was used to produce a macropolyol with an average molar mass of 4000 g·mol−1 by changing the proportions of the reactants according to Table 1.
The same protocol as that of Example 1 was used to produce a macropolyol with an average molar mass of 2000 g·mol−1 by changing the proportions of the reactants according to Table 1.
The same protocol as that of Example 1 was used to produce a macropolyol with an average molar mass of 1000 g·mol−1 by changing the proportions of the reactants according to Table 1.
Macropolyol is introduced with one or more aliphatic diisocyanates into a suitable vial. The vial is closed and introduced into a Speed Mixer for 3 min at 2500 rpm. The vial is then placed in a thermostatic oven for 2 to 24 h depending on the nature of the isocyanates used. The compositions of the gel formulations are detailed in Table 2. Amounts are expressed in percentages by weight. The water contents (EWC) are given in Table 3.
aEWC water content determined by Equation 1;
bSR swelling rate determined by Equation 2
The macropolyol and polyol are introduced with one or more aliphatic diisocyanates into a suitable vial. The vial is closed and introduced into a Speed Mixer for 3 min at 2500 rpm. The vial is then placed in a thermostatic oven for 2 to 24 h at 80° C. depending on the nature of the isocyanates used. The compositions of the gel formulations are detailed in Table 4. Amounts are expressed in percentages by weight. The water content is given in Table 5.
bEWC water content determined by Equation 1;
bSR swelling rate determined by Equation 2
The macropolyol (and polyol if needed) are introduced into a vial, named A, with 75% of the total solvent volume, and homogenized in a Speed Mixer for 2 min at 2500 rpm. A second vial, named B, is then prepared by mixing one or more aliphatic diisocyanates with 25% of total DMF. The vial is closed in turn and introduced into the Speed Mixer for 1 min at 2500 rpm. The contents of B are poured into A and homogenized. The closed vial is left for 5 min at room temperature before being placed in a thermostatic oven at 80° C. for 2 to 24 h depending on the nature of the isocyanates used. The compositions of the gel formulations are detailed in Table 4. The amounts of reagents are expressed in mass percentages without taking into account the solvent. The amount of solvent used is such that it generally represents 75 to 80 wt % of the total formulation, which is equivalent to having a 75/25 solvent/total reagents ratio. The water content of some of these gels is shown in Table 6.
aEWC water content determined by Equation 1;
bSR swelling rate determined by Equation 2
Poly(ethylene glycol) (Mw=300 g/mol) is previously dried under vacuum at 90° C. for 24 h before use. PEG (4.993 g, 17 mmol) is introduced into a 250 mL three-necked flask, topped with a semi-circular stirring paddle. The device is placed under an inert atmosphere and placed in an oil bath thermostated at 50° C., under stirring (200 rpm).
The diisocyanate, in this case isophorone diisocyanate (IPDI) (7.4 g, 7.1 mL, 33 mmol) is taken under nitrogen flow and added to the reaction medium. The reaction is thus left for 2 h until complete functionalization of the OH groups at the end of the PEG chain into urethane function. The product is characterized by 1H NMR, CES and IR and then stored in a sealed vial at 5° C.
δ(ppm), CDCl3: δ 4.96+4.70 (s, 2H, NH.; 4.18 (m, NH(CO)O—CH2); 3.62 (m, (CH2—CH2—O)n; 2.92 (m, CH—NCO and/or CH2—NCO); 1.77+0.92 (m, CH ring) 0.99 (s, CH3 *3)
The same protocol was used to produce a prepolymer between PEG300 and hexamethylene diisocyanate by changing the proportions of the reactants according to Table 6.
δ (ppm), CDCl3: δ 4.93 (s, 2H, NH); 4.22 (s, CH2—O—(CO)); 3.66 (m, (CH2—CH2—O)n); 3.31 (t, CH2—NCO); 3.16 (t, CH2—NH—(CO)); 1.62+1.52+1.43 (m, CH2—(CH2)2—CH2).
The same protocol was used to produce a prepolymer between PEG300 and 4.4′-methylenebis(cycloisocyanate) by changing the proportions of the reactants according to Table 6.
δ (ppm), CDCl3: 4.93 (s, NH); 4.22 (s, CH2—O—(CO)); 3.66 (m, (CH2—CH2—O)); 3.31 (t, CH2—NCO); 3.16 (t, CH2—NH—(CO)); 1.62+1.52+1.43 (m, CH2—(CH2)2—CH2).
The same protocol was used to produce a prepolymer between PEG200 and isophorone diisocyanate by changing the proportions of the reactants according to Table 6.
δ (ppm), CDCl3: δ 4.96+4.70 (s, 2H, NH.; 4.18 (m, NH(CO)O—CH2); 3.62 (m, (CH2—CH2—O)n; 2.92 (m, CH—NCO and/or CH2—NCO); 1.77+0.92 (m, CH cycle) 0.99 (s, CH3 *3)
The same protocol was used to produce a prepolymer between PEG200 and hexamethylene diisocyanate by changing the proportions of the reactants according to Table 6.
δ (ppm), CDCl3: δ 4.93 (s, 2H, NH); 4.22 (s, CH2—O—(CO)); 3.66 (m, (CH2—CH2—O)n); 3.31 (t, CH2—NCO); 3.16 (t, CH2—NH—(CO)); 1.62+1.52+1.43 (m, CH2—(CH2)2—CH2).
The same protocol was used to produce a prepolymer between PEG200 and 4.4′-methylenebis(cycloisocyanate) by changing the proportions of the reactants according to Table 8.
δ (ppm), CDCl3: 4.93 (s, NH); 4.22 (s, CH2—O—(CO)); 3.66 (m, (CH2—CH2—O)); 3.31 (t, CH2—NCO); 3.16 (t, CH2—NH—(CO)); 1.62+1.52+1.43 (m, CH2—(CH2)2—CH2).
The macropolyol is introduced with one or more aliphatic urethane diisocyanate prepolymers and optionally with an aliphatic diisocyanate. The vial is closed and introduced into the Speed Mixer for 3 min at 2500 rpm. The vial is then placed in a thermostatic oven for 2 to 24 h depending on the nature of the isocyanates used. The compositions of the gel formulations are detailed in Table 9. Amounts are expressed in percent by weight. The water content of some of these gels is shown in Table 10.
aEWC water content determined by Equation 1;
bSR swelling rate determined by Equation 2
The macropolyol and polyol are introduced with one or more aliphatic urethane diisocyanate prepolymers and optionally with an aliphatic diisocyanate. The vial is closed and introduced into the Speed Mixer for 3 min at 2500 rpm. The vial is then placed in a thermostatic oven for 2 to 24 h at 80° C. depending on the nature of the isocyanates used. The compositions of the gel formulations are detailed in Table 11. Amounts are expressed in percent by weight. The water content (EWC) is given in Table 12.
bSR swelling rate determined by Equation 2
The macropolyol (and polyol if needed) are introduced into a vial, named A, with 75% of the total solvent volume, and homogenized in a Speed Mixer for 2 min at 2500 rpm. A second vial, named B, is then prepared by mixing one or more aliphatic diisocyanates with 25% of total DMF. The vial is closed in turn and introduced into the Speed Mixer for 1 min at 2500 rpm. The contents of B are poured into A and homogenized. The closed vial is left for 5 min at room temperature before being placed in a thermostatic oven at 80° C. for 2 to 24 h depending on the nature of the isocyanates used. The compositions of the gel formulations are detailed in Table 13. The amounts of reagents are expressed in percentage by weight, without taking into account the solvent. The amount of solvent used is such that it generally represents 55 to 85 wt % of the total formulation. The water contents of these gels after hydration are listed in Table 14.
bSR swelling rate determined by Equation 2
The properties of the compositions detailed in Tables 8 and 9 are listed in Table 15.
adetermined by UV-VIS transmission spectroscopy at 550 nm;
bYoung's modulus, average of at least 3 analyses;
cstress at break, average of at least 3 analyses;
delongation at break; average of at least 3 analyses
The formulated and hydrated gels were also studied by AFM spectroscopy to determine the surface roughness. The properties of one of the formed gels are listed in Table 16.
atotal profile height: height between the deepest valley and the highest peak over the evaluation length,
barithmetic mean profile roughness: defined over a base length,
croot mean square profile roughness: corresponds to the standard deviation of the height distribution
The formulated and hydrated gels were also studied for wettability to determine the contact angle between the formulated lens and a drop of water. The contact angles obtained for some of these gels are listed in Table 17 and are the result of an average over 10 analyses.
Dehydration kinetics of the formulated and hydrated gels in parallel with dehydration kinetics of commercial lenses were performed. The percentages of water remaining in the gels at times of 20, 40, and 60 minutes are listed in Table 18.
atime necessary for the loss of 10% of water initially present in the network;
btime necessary for the loss of 50% of water initially present in the network
According to the protocol listed above, the oxygen permeability of hydrogels and commercial references was determined and is presented in Table 20.
aWith Dk expressed in Barrer or in 10−10 ((mL O2 · cm)/(s · cm2/cmHg))
bWith Dk/e expressed in 10−9 ((mL O2))/(s · cm2/cmHg))
| Number | Date | Country | Kind |
|---|---|---|---|
| 1859124 | Oct 2018 | FR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/FR2019/052302 | 9/30/2019 | WO | 00 |
