Ординатура / Офтальмология / Английские материалы / Biomaterials and regenerative medicine in ophthalmology_Chirila_2010

Dk (barrers)

200

Conventional hydrogels Silicone hydrogels

100

0

320 Biomaterials and regenerative medicine in ophthalmology

but in terms of measurable physical properties that could be used (on the basis of acquired clinical experience) to predict minimum acceptable baseline performance of a material, reliance was inevitably placed upon measurement by appropriate methods of its wetting properties, oxygen permeability and mechanical properties. That situation lasted until the publication of an extensive CIBA patent (Nicholson et al., 1996) that proposed a fourth type of property measurement, which is linked to lens movement on the eye – aqueous and ionic permeability.

12.6CIBA patent WO 96/31792 (Nicholson et al., 1996)

The CIBA patent WO96/31792(Nicholson et al., 1996) entitled ‘Extended wear ophthalmic lens’, published on 10 October 1996, is so extensive and raises such important issues that have subsequently dominated the commercial arena that it must be considered here in some detail – although not specifically from the viewpoint of the patent lawyer. The patent encompasses a range of structures and methodologies (e.g. siloxy macromers with polyether and fluorine-modified polyether segments, biphasic structures, surface coating), which are central to the theme of the patent. The introductory sections of the patent are informative, highlighting the main issues and giving clues to the underlying philosophy of the invention. The background highlights what is perceived to be a shortcoming in the approach taken in previously described attempts to prepare successful silicone hydrogel extended wear materials and summarises the central object of the invention:

‘… prior attempts at producing a true extended wear contact lens have been unsuccessful, either because of the effect of the extended-wear lens on corneal health or because the lens would not move on the eye. Thus, there remains a need for an ophthalmically compatible, transparent polymeric material, which is suited to extended periods of continuous contact with ocular tissue and tear fluid. An object of the invention is to provide a material having a balance of oxygen permeability, ion permeability, on-eye movement and tear exchange, all of which are sufficient for corneal health and wearer comfort during extended periods of continuous wear.’

One far-reaching feature of this patent is that the first (and arguably the most important) claim describes a principle or method upon the basis of which successful extended wear contact lenses may be designed. That is the combination of adequate oxygen permeability and adequate ionic or aqueous permeability. Much of the rest of the patent is concerned with a specific approach to the design of acceptable materials (the formation of biphasic structures) and with an appraisal of the link between ionic or aqueous permeability and lens movement on the eye.

12.6.1 Ionic permeability and biphasic structures

We now move to the principles involved in the improvements, which centre on the provision of both oxygen permeability and ion permeability in the lens together with a hydrophilic non-lipophilic coating. There are detailed descriptions of the ways in which an oxygen transmission pathway and an ion transmission pathway can be independently maintained. Their co- existence is made possible by the ‘existence of a region of substantially uniform composition which is a distinct and physically separate portion of a heterogeneous polymeric material’. More particularly, with respect to the polymeric components of a lens, two different types of phase, an ionoperm phase and an oxyperm phase are described.

The picture that emerges is of a material that permits both oxygen and ions to permeate freely from front to back surface by means of two co-continuous phases. The water content range is subsequently defined as, desirably, 15–

25% and the type of material involved is thus best described as a biphasic hydrogel with co-continuous ionopermeable and oxygen permeable phases. The term co-continuous highlights an important (in contact lens terms) and novel element of the invention since biphasic polymers frequently consist of one phase in isolated regions or droplets, within a second continuous phase; the major component normally forming the continuous phase. The oxyperm materials are described as monomers and macromers, which are siloxane- containing, fluorine-containing or carbon–carbon triple bond-containing. The ionoperm materials are simply hydrophilic monomers, which are known in hydrogel production, together with poly(ethylene glycol). These classes were already well known and have been described in the previous section.

There is nothing inherently novel in the broad description of the constituents of the invention as the novelty lies in the morphology, i.e. the existence of two co-continuous phases, coupled with optical clarity, and in the polymerisation methodology used in their formation. The achievement and maintenance of these two discrete co-continuous phases, which link the front and back surfaces of an optically clear lens, constitute the key inventive materials step of the patent. However, that is neither the only, nor arguably, the major feature of the patent. The patent is tied together with a clever knot. The co-continuous ionopermeable and oxygen permeable phases enable ion permeability and oxygen permeability to be independently modulated. This has enabled the first – and all-embracing – claim of the patent to be validated to the satisfaction of patent examiners. Thus, it established the basis upon which successful extended wear contact lenses may be designed: ‘…the combination of adequate oxygen permeability and adequate ionic or aqueous permeability’. The contribution of biphasic structures to the achievement of this requirement and the role of a ‘hydrophilic non-lipophilic’ coating to the success of an extended wear contact lens are important subsidiary aspects of

322 Biomaterials and regenerative medicine in ophthalmology

the invention. The whole patent works together to define, with supporting evidence, the behavioural requirements for successful extended wear.

These four points – (a) the need for adequate oxygen permeability to satisfy corneal oxygen requirements; (b) the need for adequate ion permeability to promote lens movement; (c) the importance of biphasic structures in achieving ionic and oxygen permeability; and (d) the value of a coating in promoting compatibility with tear components – had not been previously identified collectively. The importance of oxygen and surface properties was well established, but the need for, and the use of, ion permeability as an indicator of successful extended wear had been nowhere referred to in previous work. The clever knot that links these points together does not require specific chemical structures to achieve this. Given the problems in achieving compatibility of inherently hydrophobic silicones and hydrophilic aqueous gels, it is probable that any silicone hydrogel will show some degree of segregation of hydrophilic and hydrophobic domains. Similarly, as water content increases, ion permeability will inevitably increase – independent of specific chemistry. When the range of commercial products is examined in a following section, it will be apparent that it is extremely difficult to develop a silicone hydrogel lens – even with novel chemistry – that does not fall within the scope of the concepts outlined above.

Although this patent contains a range of materials and different chemistries, the many compositions identified can be simplistically regarded as being formed from four components, a macromer (e.g. Fig. 12.5) plus TRIS monomer (Fig.

12.4), together with two ‘solvents’ (one of which is a hydrophilic monomer).

The polymerisation involves an increase in molecular weight coupled with network formation together with a concurrent disappearance of one of the

‘solvents’ (usually N,N-dimethyl acrylamide (NNDMA); Fig. 12.3). The resultant network is left as a swollen gel in the ‘permanent’ solvent (e.g. ethanol). This polymerisation has all the features of a phase-inversion process, such as those used to form porous (sometimes asymmetric) membranes commonly used in separation processes. In the most common phase-inversion processes a mixture of solvents is evaporated from a polymer solution at differential rates. By control of the polymer precipitation and gelation process the microstructure of the resultant polymer is determined. In the process described here no evaporation occurs (if a closed mould is used) but the solvent properties change concurrently with the polymerisation by conversion of NNDMA monomer to matrix-bound copolymer. In conventional phaseinversion processes, the rate of solvent evaporation has a marked effect on the pore size and asymmetry of the product.

The consequence of successful polymerisation of this type is highlighted as the likely formation of porosity having dimensions in the region of 100 nm, reference also being made to the possible existence of an interphase region of distinct composition and structure. It is reasonable to comment that the

Relativepermeability

20

Oxygen Sodium ion

10

0

0.7

0.5

0.3

0.1

326 Biomaterials and regenerative medicine in ophthalmology

added to the three highlighted in Section 12.5 (hydrophilic TRIS variants, macromers and novel co-monomers). The first 10 years of silicone hydrogel extended wear lenses has seen a progressive change from (relatively) high modulus–low water content materials with surfaces modified by a separate discrete coating step, to lower modulus–higher water content materials with no coating. Even though these products are conceptually very different from the materials described in the CIBA patent of 1996, many of them fall within the broad behavioural criteria described in Section 12.6.2. As a result, there has been a steady stream of legal challenge, court case and royalty agreement reports in the press.

The most effective way of reviewing the technical developments is to follow the chronological appearance of commercial products (Table 12.3) commenting briefly on the underlying scientific features and advances described in their associated patents. Silicone hydrogel daily wear lenses whose oxygen transmissibilities do not meet the Holden and Mertz (1984) criteria are included since these sometimes serve to pave the way for the subsequent launch of an extended wear variant.

The first two commercial silicone hydrogels to be launched were the Bausch & Lomb PureVision (balafilcon A) lens and Focus Night & Day (lotrafilcon A) from CIBA Vision. Although they were launched within months of each other, patent issues have meant that sales of PureVision have been restricted to certain parts of the world. The PureVision material, balafilcon, is based on the approach of making more compatible versions of TRIS and employs the vinyl carbamate monomer illustrated in Fig. 12.4

(Bambury and Seelye, 1991, 1997). Unfortunately for Bausch & Lomb, CIBA Vision discovered a mid 1980s US patent (Harvey, 1985) that pre-disclosed the vinyl carbamate siloxy derivative. This surfaced among the intellectual property that came to them as part of the acquisition of Wessley-Jessen. The effect of this has been to prevent US sales of PureVision until the expiry of the Harvey patent. PureVision has a water content of 35% and a Dk of 110 barrers. It is said to have a water transport slightly (10%) in excess of that of PHEMA. This would put it above the critical minimum value of ionic and aqueous permeability for lens movement on the eye. This implies some degree of phase separation since the water transport value corresponds to a water content of 40% rather than 35%. Although Bausch & Lomb do not specifically claim that their material has biphasic characteristics, it has been shown to possess a degree of inhomogeneity (Lopez Alemany et al., 2002). In consequence, the material falls within the limits of the CIBA patent.

CIBA’sapproach,ontheotherhand,hasbeenmorefocusedonthemacromers and polymerisation methodologies discussed in relation to the 1996 patent (Section 12.6). Two broad features underpin the Night & Day material. It is claimed to be a biphasic material with co-continuous channels enabling both high oxygen permeability and high ion (e.g. sodium) permeability to be

Table 12.3 Silicone hydrogel lens materials

lenses contact wear Extended

328 Biomaterials and regenerative medicine in ophthalmology

achieved. In addition, it meets the defined minimum levels of ion or water permeation required to enable the lens to move adequately on the eye. The material (lotrafilcon A) is based on a fluoroether macromer of the general form shown in Fig. 12.5 copolymerised with TRIS monomer and NNDMA in the presence of a diluent. It is a fluoroether-based silicone hydrogel having a water content of 24% and a Dk of 140 barrers. With a water content as low as 24%, it is clear from Fig. 12.7 that neither sodium ion permeability nor aqueous permeability would approach that of PHEMA, if the structure were homogeneous. Because of the biphasic structure upon which the material is based, which allows oxygen and ionic permeability to be uncoupled (Fig. 12.9), the ionic permeability of the material exceeds that of PHEMA and consequently the lens is reported to have adequate on-eye movement.

One final difference between the PureVision and Focus Night & Day lenses lies in the surface treatment. Both are treated using gas plasma techniques but whereas Bausch & Lomb have opted for plasma oxidation, CIBA have chosen to apply a plasma coating. In the former case glassy islands are produced on the surface and on the latter a dense, 25 nm thick, high refractive index coating.

Much of the commercial realisation of this silicone hydrogel technology and especially the timing of product launches has been governed by patent ownership and litigation. Although Tanaka’s monomer (3-methacryloxy-2- hydroxypropyloxy) propyl-bis(trimethylsiloxy)methylsilane (Fig. 12.4), was the first monomer of this type to be exemplified in the patent literature, it was not converted into a commercial silicone hydrogel in the lifetime of the patent. It formed the basis of not the first, but the third commercial silicone hydrogel lens. Tanaka’s initial intent seems to have been to use it in RGP materials, primarily in an attempt to improve surface properties, although there is no evidence that it was successful in that role. Its use in silicone hydrogels did not come until the original 1979 patent had expired 25 years later. Despite the fact that the patent does contain details of silicone hydrogel lenses, these have proved very difficult to replicate using the synthetic methodologies described. In a well-thought out strategy, workers at Vistakon developed a much improved synthesis for the Tanaka monomer and were thus able to use it as a key component of Acuvue Advance (galyfilcon A), which was launched in 2004 upon the expiry of the original patent.

Galyfilcon A has a higher water content (47%), a lower Dk (60 barrers) and a much lower modulus than the two initial materials. Whereas both

PureVision and Focus Night & Day are FDA approved for overnight use,

Acuvue Advance is only approved for daily wear. The silicone hydrogel matrix is based on a combination of Tanaka’s monomer, copolymerised with HEMA and NNDMA (Fig. 12.3), together with a simple siloxy macromer.

The siloxy macromer is effectively a silicone rubber chain approximately 11 units long with a polymerisable methacrylate unit at the end of the chain.