GB2619349A - Silicone macromonomers, contact lenses and related methods - Google Patents

Abstract

A polysiloxane macromonomer of general formula [1]: wherein: p is 1-500, preferably 2-20; n is 1-500; m is 1-50; R is H or CH3. Also disclosed is a method of making the polysiloxane macromonomer; an ophthalmic lens comprising the polysiloxane macromonomer; and a silicone hydrogel comprising the polysiloxane macromonomer.

Description

SILICONE MACROMONOMERS, CONTACT LENSES AND RELATED METHODS The present invention relates to a novel polysiloxane macromonomer, a method of production thereof and an ophthalmic lens, particularly a contact lens and more particularly a silicone hydrogel contact lens comprising the reaction product of a polymerizable composition comprising the macromonomer.

Background Art

Polysiloxane macromonomers have been described as being useful in both rigid and soft contact lenses. Some have indicated that fluorine-groups may increase oxygen permeability of contact lens copolymer materials, as well as increasing lens hardness and heat resistance for rigid contact lenses (e.g., see US patents 4,433,125 and 4,686,267). In addition, fluorine-containing polysiloxane macromonomers have been described as being useful in soft contact lenses, for example, see US patent 5,760,100 or PCT Publication No. W02006026474. It has been suggested that fluoro-groups may help provide corneal staining resistance for silicone hydrogel contact lenses.

However, the inclusion of fluorine in macromonomers presents problems. It introduces complexity into the process of manufacture of the macromonomer and it adds cost both due to the raw materials and the additional complexity resulting in incorporating the fluorine containing groups.

As silicone hydrogel contact lenses improve, it is desirable to develop new monomeric components to impart the silicone hydrogel contact lenses with desirable ophthalmic properties, including without limitation, oxygen permeability, modulus, water content, and lens surface wettability. Thus, new polysiloxane macromonomers are desirable to help develop new silicone hydrogel contact lenses.

Summary

The present invention addresses this need by providing a new polysiloxane macromonomer that is free of fluorine-containing groups.

Accordingly, in a first aspect of the present invention, there is provided a polysiloxane macromonomer of general Formula (1):

O R2 0 \ / H

cro,-....w.1.0.----,-0,-----...."-si---0_40) ( sio -si---------0-------°yN '''''''0 H 1 n I in/ \ 0 (1) wherein: p is from 1 to 500, preferably from 2 to 20, more preferably from 5 to 10; ne, preferably from 1 to 500, more preferably from 80 to 250; rri1, preferably from 1 to 50, more preferably from 1 to 15; Ri = H or CH3; and R2 = H or CH3.

The macromonomer preferably has a number average molecular weight distribution (Mn) of from 12,000 to 20,000 Da, preferably from 14,000 to 17,000 Da, wherein Mn is measured by gel permeation chromatography (GPC).

In a second aspect of the present invention, there is provided a macromonomer composition comprising the polysiloxane macromonomer of the first aspect, wherein the macromonomer comprises less than 5.0% impurities as measured by GPC. It is preferred that the amount of impurities is less than 4.0% and more preferably less than 3.8%.

In a third aspect of the present invention, there is provided a macromonomer composition comprising the polysiloxane macromonomer of the first or second aspect, wherein the macromonomer has an end group content of between 0.8 and 2, and preferably between 1 and 1.8, more preferably between 1.2 and 1.6. The end group content is defined as the corrected peak height ratio of a first peak of an FTIR spectrograph representing the C=0 groups to a second peak of an FTIR spectrograph representing the SiCH3 groups. This numeric value provides a link between the functional groups and length of the silicone chains in the polysiloxane macromonomer composition. For a given target molecular weight, the end group content provides a measure of the average functionality of the macromonomers in the macromonomer composition.

In a fourth aspect of the present invention, there is provided a method of making the polysiloxane macromonomer of the first aspect, wherein the method comprises: reacting 1,3,5,7-tetraethylcyclotreasiloxane, octamethylcyclotetrasiloxane and 1,3-bis(3- (2-hydroxyethoxy)propyl)tetramethyldisiloxane to form a hydrosilyl-group containing polysiloxane; reacting the hydrosilyl-group containing polysiloxane with a polyethyleneglycol allylmethylether to form a polyethylene glycol methyl ether containing polysiloxane; and reacting the polyethylene glycol methyl ether containing polysiloxane with a 2-isocyanatoethyl (meth)acrylate to form the polysiloxane macromonomer.

In a fifth aspect of the present invention, there is provided an ophthalmic lens, preferably a contact lens, more preferably a silicone hydrogel contact lens comprising the reaction product of a polymerizable composition comprising the macromonomer of the first aspect or the macromonomer composition of the second or third aspects.

In a sixth aspect of the present invention, there is provided a silicone hydrogel contact lens, comprising the reaction product of a contact lens formulation comprising the polysiloxane macromonomer of the first aspect or the macromonomer composition of the second or third aspects; a second polysiloxane monomer selected from Formula 2 or Formula 3 as defined below, or both; an N-vinyl-monomer selected from N-vinyl pyrrolidone or N-vinyl N-methyl acetamide, or both; and optionally a hydroxyalkyl methacrylate monomer, at least one type of crosslinker, a polymerisation initiator, a tinting agent, a UV absorbing compound, or combinations thereof.

Detailed description

The present invention relates to a polysiloxane macromonomer of general formula (1): R2 0 \ / rn 0 n 0

O (1)

wherein: p is from 1 to 500; Ri = H or CH3; and R2 = H or CH3.

The structural formula of the macromonomer is shown as a block structure of the two types of siloxane units. However, this is representational. The siloxane units can be in the form of blocks or preferably can contain random structures. The formula provides the ranges of each siloxane unit in the macromonomer, which are set out below.

The molecular weight will depend on the number of siloxane groups in the macromonomer. It is preferred that n is from 1 to 500, preferably 20 to 350, more preferably 80 to 250 and particularly preferably 120 to 160.

It is preferred that m is from 1 to 50, preferably from 1 to 15 and particularly preferably from 3 to 9 It is preferred that the value of n is greater than the value of m. The ratio of n:m is preferably from 1:1 to 250:1, more preferably from 5:1 to 100:1, yet more preferably from 13:1 to 55:1.

It is preferred that p is from 1 to 30, more preferably from 2 to 20 and particularly preferably from 5 to 10.

It is preferred that the average molecular weight (Mn) of the polysiloxane macromonomer is greater than 5,000 Da, preferably 8,000 to 30,000 Da, more preferably 12,000 to 20,000 Da and yet more preferably 14,000 to 17,000 Da.

The macromonomer composition comprises the polysiloxane macromonomer described above. The macromonomer composition typically has an impurity level of less than 5%, preferably less than 4% and more preferably less than 3.8% as measured by GPC.

The impurities typically take the form of unreacted components of the reaction or partially reacted components. Impurities may include non-functional polysiloxane oligomers. However, impurities do not include monofunctional macromonomers which form as a byproduct of the process of forming the polysiloxane macromonomers of the present invention.

The macromonomer composition has an end group content of between 0.8 and 2.0, and preferably between 1.0 and 1.8 and more preferably between 1.2 and 1.6. The end group content is the ratio of corrected height of peaks representing C=0 groups to SiCH3 groups as measured by FTIR spectrometry.

The macromonomer in the macromonomer composition of the present invention preferably has an average molecular weight of 12,000 to 20,000 Da. It is also preferred that the macromonomer composition is mainly comprised of difunctional macromonomers, although some other functionalities, such as monofunctional macromonomers will be present. Compositions having the claimed end group content are identified as containing macromonomers having the preferred balance of average molecular weight and functionality to be particularly useful in the formation of silicone hydrogel contact lenses.

The end group content is measured as follows: (1) Dissolve the macromonomer sample in analytical grade ethanol at 1:1 weight ratio.

(2) Use a Nicolet iS50 FTIR manufactured by Thermo Fisher Scientific, set up as: Number of Scan= 32, Resolution = 4, Scan range between 1000 to 2500 cm* (3) Insert an empty PTFE FTIR card and scan background.

(4) Take out the IR card and spread 150 pl of macromonomer solution at the centre of the card. Let the ethanol evaporate. Insert the FTIR card with the sample in the machine to the transmission base position and run the sample.

(5) Analyse the data as follows: integrate the peak with selected wavelength range to establish the baseline, use the baseline from the integration to measure the baseline corrected peak height, then use the corrected peak height for the calculation. Peak 1 = 1726 cm-I, integrate between 1764 to 1668 cm-' (C=0 group). Peak 2 = 1412 cm-1, integrate between 1497 to 1337 cm-1 (SiCH3 group).

Calculate peak ratio as per the following expression: End group content = Corrected Height of Peak 1/Corrected Height of Peak 2.

An example FTIR spectra is shown in Chart 1.

Chart 1. Example of FTIR spectrum End group content = Corrected Height of Peak 1/Corrected Height of Peak 2 Peak 1 = 1725 cm 1, from 1764 to 1668 cm 1 (C=0 group) Peak 2 = 1412 cm 1, from 1497 to 1337 cm-1 (SiCH3 group) Dividing 0.320 by 0.250 = 1.28 End group content = 1.28 The macromonomer composition has a viscosity in the range of 300 to 1000 mPa.s, preferably 450 to 750 mPa.s as measured at 23°C using Brookfield Spindle Viscometer and cone spindle at speed 2.5rpm.

The macromonomer composition is colourless. In accordance with the present invention, a colourless composition is one with a value of less than 100 as measured on the APHA colour scale (according to ASTM D1209).

The macromonomer composition has a refractive index at 23°C of 1.412 to 1.418, as measured by refractometer by placing a drop of the material on the surface of the prism at 15 23°C.

The water content of the macromonomer composition is preferably less than 0.5wt%, more preferably less than 0.3wt%, measured on Karl Fischer Titrator.

The presence of known polymerisation inhibitors such as monomethylether hydroquinone (MEHQ) or butylated hydroxy toluene (BHT) can affect the polymerisation of lens formulations made using the macromonomer composition. The macromonomer composition preferably contains less than 200ppm BHT, and preferably less than 150ppm BHT, and more preferably less than 125ppm BHT.

Additionally, the composition shall preferably contain less than 100ppm of MEHQ, preferably less than 75ppm MEHQ and more preferably less than 55ppm MEHQ.

Other polymerisation inhibitors are known to the skilled person. It is preferred that the composition comprises less than 50ppm, preferably less than 10ppm of other polymerisation inhibitors.

It is particularly preferred that the total amount of polymerisation inhibitors, including BHT and MEHQ, in the composition is less than 200ppm and preferably less than 100ppm.

The polysiloxane macromonomer or the macromonomer composition of the present invention can be used in the formation of ophthalmic lenses, particularly contact lenses and more particularly silicone hydrogel contact lenses. For example, an ophthalmic lens formulation can comprise the polysiloxane macromonomer of Formula 1, in addition to one or more other siloxane monomers or polysiloxane macromonomers, one or more hydroxy-containing monomers, and one or more N-vinyl amide-containing monomers. In addition, the ophthalmic lens formulation may comprise a polymerization initiator, and one or more bifunctional, trifunctional, or tetrafunctional crosslinkers.

As a further example, a silicone hydrogel contact lens can comprise the reaction product of a contact lens formulation comprising the polysiloxane macromonomer of Formula 1; a second polysiloxane monomer of Formula 2 or Formula 3 (below), or both; an N-vinyl-monomer selected from N-vinyl pyrrolidone or N-vinyl N-methyl acetamide, or both; and optionally, a hydroxyalkyl methacrylate at least one type of crosslinker, a polymerisation initiator, a tinting agent, or a UV absorbing compound, or combinations thereof. The tinting agent can be either a polymerisable dye or it can include particles of pigments. The UV absorbing compound can be a benzotriazole compound or a benzophenone compound.

Suitable polysiloxane monomers include those of Formula 2 and Formula 3.

Formula 2: Formula 3: H Si, a wherein n is 10 to 15, A silicone hydrogel contact lens of the present invention is a copolymeric material comprising units derived from the polysiloxane macromonomer of Formula 1.

The formulation is suitable for making fully cast molded lenses, rods or buttons for lathing lenses and lenses fabricated using a hybrid process where one surface is cast molded and the other lathed.

For a fully cast molded contact lens, the silicone hydrogel contact lens can be made by placing a lens formulation in a contact lens mold assembly, exposing the contact lens mold assembly to heat or light to cause the lens formulation to polymerise, separating the polymerised contact lens from the contact lens mold assembly, washing the separated polymerised contact lens to remove unreacted monomers, diluents, and the like, and packaging the washed polymerised contact lens in a contact lens package containing a saline packaging solution. The packaged contact lens can then be sterilized, such as by autoclaving.

Example synthesis of Macromonomer The method of synthesis is described with reference to the drawings in which: Figure 1 shows a schematic synthetic route of the process; Figure 2 shows the ring-opening polymerization; Figure 3 shows the hydrosilylation; and

Figure 4 shows the introduction of methacrylate.

The macromonomer composition of the present invention can be synthesized using various methods. One general method of synthesis of a polysiloxanediol having hydrosilane groups is disclosed in Synthesis Example 1 of W02006/026474.

Other similar suitable methods are known to the skilled person. These methods employ reagents and reactions, synthesis strategies and techniques which are conventional and well known, such as in silicone polymer chemistry. An example of the synthetic steps involved and possible synthetic methods for the silicone compound of the first aspect of the present invention comprises the following three-step reactions illustrated in Figure. 1. However, it is recognized that there are alternate methods of synthesis that may be utilized to produce a compound within the scope of the present invention.

The above-described reaction formula contains the following details as an example of suitable reaction conditions.

A ring-opening polymerization is undertaken of a mixture of a cyclic siloxane with hydrosilane groups (Si-H) such as 1,3,5,7-tetraethylcyclotreasiloxane, and a cyclic siloxane with hydrocarbon groups, such as octamethylcyclotetrasiloxane, and disiloxane with hydroxyalkyl groups at both ends, such as 1,3-bis(3-(2-hydroxyethoxy)propyl)tetramethyldisiloxane. The reactants are dissolved in an organic solvent, such as chloroform, toluene or benzene, and the reaction is performed using an acidic catalyst, such as sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or acidic clay to obtain hydrosilyl-group-containing polysiloxane compounds having hydroxyl groups at both ends.

Siloxane compounds with various degrees of polymerization and introduction ratios of hydrosilyl groups can be obtained by changing feed ratios of each cyclic siloxane and disiloxane compounds used.

After reaction, the acidic catalyst can be neutralized with a basic compound, such as MgO, aluminum oxide, hydrotalcite, or repeatedly washing with water until the pH of the mixture becomes neutral. The residual liquid can be purified through precipitation in methanol or ethanol, followed by removal of volatile components under vacuum to give a transparent viscous liquid. This liquid is siloxanediol having hydrosilane groups.

Hydrophilic components can be introduced by a hydrosilylation reaction by adding an unsaturated hydrocarbon group containing hydrophilic compound, such as polyethyleneglycol allylmethylether, to the above intermediate containing hydrosilane groups using a transition metal catalyst, such as a platinum based catalyst (such as Speier's and Karstedt's catalysts) or a rhodium based catalysis (such as [RhCI(nbd)]2).

The unreacted hydrophilic polyethyleneglycol allylmethylether can be removed by washing with organic solvent, such as acetone, acetonitrile, methanol or a mixture of organic solvent and water, to obtain a transparent viscous liquid, namely siloxanediol with hydrophilic polyethyleneglycol side chains.

The bi-functional macromonomers may be produced from this intermediate compound using conventional and well-known chemical synthesis techniques. For example, the above siloxanediol having polyethyleneglycol components, can be reacted with an isocyanate-substituted acrylate or an isocyanate-substituted methacrylate, such as 2-isocyanatoethyl methacrylate, 2-isocyanatoethyl acrylate, in the presence of a catalyst, for example, dibutyltin dilaurate, ferric acetylacetonate or zinc 2-ethylhexanoate catalyst, at conditions effective to undergo reaction at both ends. Subsequently, the resulting liquid can be washed with organic solvent, such as acetone, acetonitrile, methanol or their mixture with water, to remove unreacted residues and obtain a transparent viscous liquid.

The resulted viscous liquid is the proposed bifunctional siloxanyl (meth)acrylate macromonomer.

Further examples of reaction process details can be divided by reaction steps. Step 1, Ring opening polymerization is illustrated in Figure 2.

A mixture of octamethylcyclotetrasiloxane, 1,3,5,7-tetramethylcyclotetrasiloane,1,3-bis(3- (2-hydroxyethoxy)propyl)tetramethyldisiloxane and chloroform were stirred in a reactor. To the solution, methanesulfonic acid is added as catalyst and stirred at 25°C for 24 hrs. Magnesium oxide is added, and stirred for 1.5 hrs at room temperature. The reaction mixture is then filtered and the chloroform evaporated using a rotary evaporator. The residual liquid is dissolved in dry acetone and reprecipitated in methanol, followed by removal of volatile components under vacuum to give a transparent viscous liquid, which is siloxanediol having hydrosilane groups.

Step 2, Hydrosilylation is illustrated in Figure 3.

To the liquid from step 1, methoxy polyethyleneglycol allylether (MW400), isopropyl alcohol, potassium acetate and chloroplatinic acid are added and stirred at 50°C for 3 hrs. After the reaction, the isopropyl alcohol is removed using a rotary evaporator, followed by washing with a mixture of methanol and water three times. Further removal of volatile components under vacuum gives a transparent viscous liquid, which is siloxanediol having polyethyleneglycol components.

Step 3, Introducing methacrylate groups is illustrated in Figure 4.

To the liquid product from step 2, dry 2-butanone, 2-isocyanatoethyl methacrylate and dibutyltin dilaurate are added and stirred at 35°C for 5 hrs, methanol added and then further stirred for 2hrs. Subsequently, the 2-butanone is removed using a rotary evaporator, followed by washing with a mixture of methanol and water for three times. Further removal of volatile components under vacuum gives a transparent viscous liquid, which is targeted product of bifunctional siloxanyl methacrylate macromonomer.

The resulting macromonomer composition has an impurity level of less than 3.8% as measured by organic GPC using polystyrene as standard, and chloroform as mobile phase.

Claims (11)

1. Claims 1. A polysiloxane macromonomer of general Formula (1): S\q R2 0 I 11 I 11N \ /SiO Si 0 0O (1)wherein: p is from 1 to 500, preferably from 2 to 20; nal, preferably from 1 to 500; preferably from 1 to 50; Ri = H or CH3; R2 = H or CH3.
2. 2. A polysiloxane macromonomer of claim 1, wherein p is from 5 to 10, n is from 80 to 250 and m is from 1 to 15.
3. 3. A polysiloxane macromonomer of claim 1 or claim 2, wherein Mn is from 12,000 to 20,000 Da, preferably from 14,000 to 17,000 Da, wherein Mn is measured by GPC.
4. 4. A macromonomer composition comprising the polysiloxane macromonomer of any one of claims 1 to 3 and less than 5% impurities as measured by GPC.
5. 5. A macromonomer composition comprising the polysiloxane macromonomer of any one of claims 1 to 3 and having an end group content of between 0.8 and 2.0, preferably 1.2 to 1.6 as measured by FTIR spectrometry.
6. 6. A macromonomer composition as claimed in claim 4 or claim 5, wherein the composition has a viscosity of 300 to 1000 mPa.s and a water content of less than 0.5 wt%.
7. 7. A macromonomer composition as claimed in any one of claims 4 to 6, wherein the composition comprises less than 200 ppm polymerisation inhibitors.
8. 8. A method of making the polysiloxane macromonomer of any one of claims 1 to 3, wherein the method comprises: reacting 1,3,5,7-tetraethylcyclotreasiloxane, octamethylcyclotetrasiloxane and 1,3-bis(3-(2-hydroxyethoxy)propyl)tetramethyldisiloxane to form a hydrosilyl-group containing polysiloxane; reacting the hydrosilyl-group containing polysiloxane with a polyethyleneglycol allylmethylether to form a polyethylene glycol methyl ether containing polysiloxane; and reacting the polyethylene glycol methyl ether containing polysiloxane with a 2-isocyanatoethyl (meth)acrylate to form the polysiloxane macromonomer.
9. 9. An ophthalmic lens, preferably a silicone hydrogel contact lens, comprising the reaction product of a polymerizable composition comprising the macromonomer of any one of claims 1 to 3 or the macromonomer composition of any one of claims 4 to 7.
10. 10. A silicone hydrogel contact lens as claimed in claim 9, the polymerizable composition additionally comprising: one or more other siloxane monomers or polysiloxane macromonomers; one or more hydroxy-containing monomers; and one or more N-vinyl amide-containing monomers.
11. 11. A silicone hydrogel contact lens, comprising the reaction product of a contact lens formulation comprising: the polysiloxane macromonomer of any one of claims 1 to 3; a second polysiloxane monomer of Formula 2: or Formula 3: N 0Hwherein n is 10 to 15, or both; an N-vinyl-monomer selected from N-vinyl pyrrolidone or N-vinyl N-methyl acetamide, or both; and optionally; a hydroxyalkyl methacrylate monomer, at least one type of crosslinker, a polymerisation initiator, a tinting agent, a UV absorbing compound, or combinations thereof.