Low Modulus Fluorosiloxane-Based Hydrogels for Contact Lens

Chapter 19

Low Modulus Fluorosiloxane-Based Hydrogels for Contact Lens Application J . Künzler and R. Ozark

Downloaded by UNIV LAVAL on October 27, 2015 | http://pubs.acs.org Publication Date: May 4, 2000 | doi: 10.1021/bk-2000-0729.ch019

Department of Polymer Development, Bausch and Lomb Inc., 1400 North Goodman Street, Rochester, NY 14692-0450

Novel methacrylate functionalized fluorinated-siloxy silanes were evaluated for potential use in hydrogels for extended wear contact lens application: methacryloyloxypropyl-tris(3-(2,2,3,3,4,4,5,5-octafluoro pentoxy)propyldimethylsiloxy)silane (Tris(F)), methacryloyloxypropyldi(3-(2,2,3,3,4,4,5,5-octafluoropentoxy)propyldimethylsiloxy)methyl silane (Di(F)), and 1-(methacryloyloxypropyl)-3-(3-(2,2,3,3,4,4,5,5 -octafluoropentoxy)propyl)tetra-methyldisiloxane (Mono(F)). The methacrylate fluorinated-silanes were synthesized by the hydrosilation reaction of methacrylate capped hydrido-siloxy silanes with allyloxyoctafluoropentane. An alternate synthetic procedure for Mono(F) was developed. Radical bulk polymerization of the methacrylate functionalized fluorinated-siloxy silanes with hydrophilic monomers, such as dimethylacrylamide, resulted in transparent hydrogels possessing a wide range of water contents, high oxygen permeability, and a low modulus of elasticity.

To design a successful hydrogel for contact lens application, the candidate polymer must satisfy a number of material requirements (1-3). The material must be optically transparent, possess chemical and thermal stability and be biologically compatible with the ocular environment. The material must also possess a low modulus of elasticity for patient comfort and high tear strength for lens handling durability. In addition, it is important that the material can be bulk polymerized and processed utilizing current contact lens manufacturing techniques (4). Finally, the material must be permeable to oxygen. Due to a lack of blood vessels within the corneal framework, the cornea obtains oxygen from the atmosphere. Without an adequate supply of oxygen, corneal edema may occur resulting in a number of adverse physiological responses (5-6). The key intrinsic material property that is a measure of oxygen diffusion is oxygen

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© 2000 American Chemical Society

In Silicones and Silicone-Modified Materials; Clarson, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

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permeability (Dk, where D is the diffusion coefficient and k is a proportionality coefficient called the Henry's law coefficient). There is currently no generally accepted level o f D k for extended wear application. Many practitioners believe, however, that for a 0.1 mm thick lens, a D k o f 100 barrers ((cm302(STP)cm)(sec"^cm'^mrnHg"l)) is suitable for extended wear application (5-6). There exist two basic methods for the development o f hydrogels with high oxygen permeability. The first approach involves the development o f high water content hydrogels. The high water content lens material increases the supply o f oxygen to the cornea (the higher the water content-the higher the oxygen permeability o f the hydrogel)(/). The second approach for the development o f high oxygen permeable hydrogels involves the design o f silicone based hydrogels. Polydimethylsiloxane ( P D M S ) due to its low modulus o f elasticity, optical transparency and high oxygen permeability is an ideal candidate for use in contact lens materials. P D M S possesses an oxygen permeability that is about 50 times higher than the oxygen permeability o f the hydrogel p o l y ( H E M A ) and 15 times higher than the high water content hydrogels (7). There are, however, several limitations to overcome before designing hydrogels based on P D M S . The primary obstacle is that P D M S is hydrophobic and insoluble in hydrophilic monomers. Thus, when attempts are made to copolymerize methacrylate functionalized siloxanes with hydrophilic monomers, opaque, phase-separated materials are usually obtained. In many cases, a co-solvent such as hexanol or isopropanol can be used to solubilize the siloxane and hydrophilic monomer. In addition, the copolymerization o f methacrylate functionalized silicones with hydrophilic monomers results in materials with a reduction in water content, loss o f surface wettability and an increase in lipophilic character. Lipid uptake can lead to a loss in material wettability. In previous work, we had shown that copolymers o f methacrylate end-capped fluoro substituted siloxanes with varying concentrations o f fluorinated methacrylates, resulted in transparent, oxygen permeable, low water (90%) as demonstrated by *H N M R and G C analysis, however, the results were not reproducible and scale-up was unsuccessful. An unknown was observed in both the *H N M R and G C that increased significantly in concentration at scale-up. The H N M R showed two singlets at d 1.14 ppm and 8 1.16 ppm and a multiplet at 8 2.5ppm. We were unable to identify this impurity by GC MS due to its low volatility, l


CH

3


Tris (F)

Di(F)

Mono(F)

CH,

CH. 0-(CH ). 2

i

_

C

H

CH,

3

CH

3

1

S i - O - -Si — O - — Si — O - S i - ( C H ) i

CH

2

i

3

_CH

3

_

L

X

CHi

1

CH

4

3

y

CH, CH,

O—CH—(CF )-H 2

F(Si) Figure 1. Molecular structure of Tris(F), Di(F), Mono(F) and FSi.


302

|H

CI

I

SI

CI

CI—Si

+

" I

O

3

H

CH,

CI

H20 TEA

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1

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2

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Pt THF/Dioxane

Si(CH ) -(CH ) -0-CH -(CF ) -H 3

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2

2

3

2

2

4

0

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^Sl—O

Si(CH ) -(CH ) -0-CH -(CF ) -H 3

2

2

3

2

2

4

O Si(CH )-(CH ) -0-CH -(CF ) -H 3

2

3

2

2

4

Major Product

Si(CH ) -(CH ) -0-CH -(CF ) -H 3

CH,

2

2

3

2

2

4

O S — O

Si(CH ) -(CH ) -0-CH -(CF ) -H 3

2

2

3

2

2

4

0 Si(CH )-(CH ) -0-CH -(CF ) -H 3

2

3

2

2

4

Minor By-product Figure 2. Synthetic procedure used to prepare the Tris(F) showing the reduced methacrylate by-product.


303


nor were we able to isolate the impurity by column chromatography. The synthesis of Di(F) was completed using the same synthetic procedure with identical results. We then decided to explore the synthesis of Mono(F) using the same synthetic procedure. This monomer was selected primarily as a model reaction in an attempt to elucidate the unknowns that formed during the synthesis of Tris(F) and Di(F). Due to the higher volatility of Mono(F), GC-MS identification evaluation of the unknowns was considered possible. The synthesis consisted of first preparing the methacryloyloxypropyltetramethyldisiloxane. This was accomplished by the hydrolysis reaction of methacryloyloxypropyldimethylchlorosilane with a large excess of dimethylchlorosilane, followed by hydrosilation with allyloxyoctafluoropentane. Analysis of the resultant Mono(F) by *H N M R again shows the two identical singlets at d 1.14 ppm and d 1.16 ppm and a multiplet at d 2.5 ppm. GC MS analysis shows one major impurity that was identified as a methacrylate reduction by-product. This impurity forms through the reaction of a silicone hydride with the methacrylate carbonyl. The reduced methacrylate was present at a 15-20% concentration, and as shown by N M R analysis, appears to be the primary impurity obtained in the synthesis of both Tris(F) and Di(F) (Figure 2). We presently believe that this impurity can be minimized through the use of a large excess of allylic fluoro ether during the hydrosilation reaction. Efforts to minimize this impurity by careful control of the reaction conditions (temperature, allylether concentration, solvent, catalyst concentration and type) are presently under evaluation. We also explored an alternate synthesis of Mono(F). Figure 3 outlines the four step synthetic procedure used to prepare Mono(F). The first step consisted of the rhodium catalyzed hydrosilation reaction of tetramethyldisiloxane with one equivalent of allyloxytrimethylsilane (17). The next step consisted of the platinum catalyzed hydrosilation of the disiloxane silicone hydride intermediate with allyloxyoctafluoropentane. Both hydrosilation reactions were monitored for extent of reaction (loss of Si-H) by *H N M R spectroscopy. The third step in the reaction consisted of an acetic acid catalyzed deprotection of the trimethylsilyl group using a 10% solution of acetic acid in methanol. The deprotection was quantitative with no apparent degradation of the siloxane linkage. The final step consists of the reaction of the deprotected disiloxane (used as is) with methacryloyl chloride. The final purified product, as expected, is free of the methacrylate reduction by-products. Hydrogel Formulation. The mechanical and physical properties that we hoped to achieve in this study included a Young's modulus between 30g/mm and 100g/mm , a D K greater than 50 barrers, and water contents between 20 and 60%. These physical and mechanical property objectives were chosen on the bases of clinical experience from a variety of commercial and experimental lens materials (18). Table I summarizes the mechanical and physical property results for films cast from Tris(F), Di(F) and Mono(F) with varying concentrations of dimethylacrylamide (DMA) using the photoinitiator Darocur 1173 (Novartis). All of the films were transparent without the use of a co-solvent. In contrast, films cast with varying concentration of D M A from a non-fluorinated TRIS, or Tris(F) possessing a fully 2


2

CH, Si — O

Si — H

CH,

CH,

„OTMS

1

Rh

CH,

CH,


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Si

O

CH,

Si-H CH,

Pt

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4

CH, (CF ) H

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4

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4

CH,

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Figure 3 Modified synthetic procedure used to prepare the Mono(F).


4

305

Table I. Mechanical and physical property results for formulations based on the methacrylate functionalized fluoro-siloxy silanes (Tris(F), Di(F), Mono(F)) Tear Composition Modulus DK % %IPA (g/mm) (w/w) Loss H0 (g/mm ) 2


2

Tris(F)/Dma 80/20 70/30 60/40

12.4 11.5 11.1

15 31 42

113 89 113

3.3 2.7 2.0

40 36 36

Di(F)/Dma 70/30

13

32

24

3.0

42

Mono(F)/FSi/Dma 70/0/30 60/0/40 50/0/50

12 7.5 8.9

27 33 54

25 40 25

5.6 2.5 2.8

35 31 37

104 3.1 0/70/30 6.7 34 192 3.5 70 100 20/50/30 5.5 33 65 3.1 40/30/30 5.0 29 34 D K in units of [(cm (^(STP) cm)/(sec. c m mmHg)] 10" . All formulations contain 0.5% Darocur 1173 as U V initiator and 0.5% ethyleneglycol dimethacrylate as crosslinker. 3

2

11

fluorinated graft [-(CF ) -F], resulted in phase separated opaque films. No morphological data is presently available on the fluoro-siloxy silane copolymers films, but the data strongly indicates that the incorporation o f the terminal [-CF -H] functionality reduces or eliminates phase separation that occurs with conventional polydimethylsiloxanes. W e attribute this to the hydrogel bond interactions between the terminal [-CF -H] and the amide linkage of D M A . In this study the kinetics o f polymerization was monitored by N I R spectroscopy. For all films cast, a complete loss o f vinyl was shown to occur following one hour o f irradiation (3,500 jnW/cm ). The low level o f isopropanol extractables also indicates a high incorporation o f methacrylate as well as a high level o f monomer purity. 2

X

2

2

2

Hydrogels possessing a wide range in water content were obtained. A n increase in the concentration o f D M A resulted in, as expected, a significant increase in water content for all fluoro-siloxy monomers tested. F o r example, the 80/20 (Tris(F)ZDMA) copolymer resulted in a water content o f 15% and the 60/40(Tris(F)/DMA) copolymer gave a water content o f 42%. N o statistical trend in tear strength was observed. Modulus values, however, were consistently higher for the Tris(F) based formulations. Surprisingly, the D k for all three fluoro-siloxy monomers remained relatively constant. The 70/30(Tris(F)/DMA) and 70/30 ( M o n o ( F ) / D M A ) gave respective D k values o f 35 and 36. This was a very significant result in that it directed our research efforts to focus on the Mono(F) copolymers, since not only was



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the modulus lower for these copolymers, but the Mono(F) alternate synthesis procedure yields a more reproducible and higher purity product. Although all of these films resulted in low modulus, low extractables, and acceptable levels of water content and transparency, the Dk for these materials is below that required for extended wear application. In an attempt to design formulations with higher Dk and low modulus, we copolymerized a DP 100 methacrylate end capped 25 mol % fluoro side-chain siloxane (F-Si)(Figure 1) with D M A and varying concentrations of Mono(F). Table I summarizes the mechanical and physical property results for films prepared from F-Si, D M A and Mono(F). The mechanical data shows that with an increase in the concentration of Mono(F), a significant reduction in modulus occurred. Similar trends were also obtained with other silicone hydrogel formulations, i.e., reduction in modulus while maintaining moderately high levels of DK. The oxygen permeability for these formulations is in the generally acceptable region for extended wear application. We believe the Mono(F) acts as a polymerizable diluent in these systems, thus lowering the T of the final polymers. g

Summary Three novel methacrylate functionalized fluoro-siloxy silanes were evaluated for potential use in hydrogels for extended wear contact lens application: (Tris(F)), (Di(F)), and (Mono(F)). The methacrylate fluoro-siloxy silanes were synthesized by the hydrosilation reaction of methacrylate capped hydrido-siloxy silane with allyoxyoctafluoropentane. Poor lot to lot reproducibility was achieved using this synthetic scheme due primarily to a methacrylate reduction side-reaction. An alternate synthetic procedure was developed for Mono(F). Radical bulk polymerization of the methacrylate functionalizedfluorinated-siloxysilanes with hydrophilic monomers, such as dimethylacrylamide, resulted in transparent hydrogels possessing a wide range of water contents, high oxygen permeability, and a low modulus of elasticity. References 1.

2. 3. 4. 5. 6. 7. 8. 9.

10.

Künzler, J. In Contact Lenses, Gas Permeable in Polymer Materials Encyclopedia; Salamone, J.C., Ed.; CRC Press: Boca Raton, Fl, 1996, p. 1497. Künzler, J.F.; McGee, J.M. Chemistry and Industry 1995, 16, 651. Friends, G.D.; Künzler, J.F.; Ozark, R.M. Macromol. Symp. 1995, 98, 619 Ruscio, D.V. Polym. Prep. Am. Chem. Soc. Div. Polym. Mat. Sci. and Eng. 1993, 69, 221. White, P. Contact Lens Spectrum 1990, p46-63. Holden, B.; Mertz, G.; McNally J. Invest. Ophthalmol. Vis. Sci. 1983, 24, 218. Polymer Handbook; Brandrup, J.; Immergut, E.H., Eds.; 3rd. Ed.; WileyInterscience: New York, 1989, p. VI 435. Künzler, J.F. Trends in Polymer Science 1996, 4, 52. Friends, G.; Künzler, J.; Ozark, R.; Trokanski, M . In ACS Symposium Series No. 540, Polymers of Biological and Biomedical Significance, Shalaby, S.W.; Williams, J.; Ikada, Y.; Langer, R., Eds.; American Chemical Society, 1993. Künzler, J.; Ozark, R. J. of Applied Polymer Science 1995, 55, 611.


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11. 12. 13.


14. 15. 16.

17. 18.

Dehmlow, E . V . ; Dehmlow, S.S. In Phase Transfer Catalysis; Ebel, H., E d . ; Verlag Chemie: Weinheim, 1983, p. 104. Fatt, I.; Rasson, J.E.;Melpolder, J.B. ICLC 1984, 14, 38. Britcher, L.J.; Kehoe, D . C . ; Matisons, J.G.; Swincer, A . G . Macromolecules 1995, 28, 3110. Lewis, L.N. J. Am. Chem. Soc. 1990, 112, 5998. Speier, J. L. Adv. Organomet. Chem. 1979, 17, 407. Marciniec, B . ; Gulinski, J.; Urbaniak, W . ; Kornetka, Z . In Comprehensive Handbook on Hydrosilation; Marciniec, B . , E d . ; Pergamon Press: Oxford, 1992. Crivello, J . V . ; Bi, D . J. Polym. Sci., Polym. Chem. 1993, 31, 2729. Bausch and Lomb in-house clinical data.


Low Modulus Fluorosiloxane-Based Hydrogels for Contact Lens

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