FOR OPHTHALMIC DEVICES

Christopher D. Wilcox

Christine Liau

Stephen Q. Zhou

Igor Valyunin

Background

[0001] This application is based on and claims priority from U.S. Provisional

Application No. 61/781,948, filed March 14, 2013, which is incorporated by reference herein.

[0002] Eye surgeries involving ophthalmic devices usually require an incision for introducing the ophthalmic device to the target location for their intended use. Often, it is desirable to make the incision size as small as possible for fast recovery and for minimizing potential post-operational complications and side effects. In order to understand this general small incision concept, the following examples are given for the purpose of illustration, but not to limit the scope of the present invention.

[0003] Intraocular lenses (IOLs) have been used as the replacement for the crystalline lens after cataract surgery and as a phakic lens which functions together with the intact crystalline lens for correcting refractive errors. To surgically implant an intraocular lens (IOL) or phakic lens into the eye, an incision is made on the cornea. It is desirable to keep the incision size as small as possible. Implanting a traditional polymethyl methacrylate (PMMA) IOL or a PMMA phakic lens requires an incision size of about 6 mm simply because the hard PMMA lens has an optical diameter of approximately 6 mm. In order to reduce the incision size, soft materials, such as silicone or soft acrylic material have been used for lenses. A soft lens can be folded in half and then implanted into an eye with an incision size of about 3 mm, The reduction in incision size has been proven in clinical studies to reduce surgically induced astigmatism, hasten wound healing, and reduce risk of infection and/or inflammation.

[0004] A corneal inlay is an ophthalmic device surgically implanted within the cornea. A corneal inlay is designed as a lens, about 2 to 3 mm in diameter, which provides a central nearsighted vision zone for presbyopic patients. The natural cornea surrounding the inlay provides the patient with the farsighted vision. The human cornea has a thickness of approximately 0.5 mm. To implant a thin inlay lens into the cornea, the first step is to make an incision on the corneal surface without cutting through the whole corneal layer. The second step is to make a pocket within the corneal layer with the initial incision as the pocket opening. The incision should have a sufficient width so that the artificial inlay lens can be introduced into the pocket. For example, if a hard corneal inlay lens, such as a PMMA lens, is used, the minimum incision size needs to be about the same as the diameter of the PMMA lens. As with an 10L, a deformable inlay lens allows a reduced incision size and, therefore, reduced surgical trauma.

[0005] Cytomegalovirus (CMV) infection of the retina, or CMV retinitis, usually leads to blindness if untreated. CMV retinitis progresses very rapidly, particularly in HIV patients, often within weeks. One of the treatments is to introduce an anti-CMV drug inside the eye by a slow release drug delivery device through the cornea or the sclera. To implant the drug delivery device into the eye, a small incision or hole is cut through the cornea. Then the drug delivery device is pushed through the incision or the hole. For this application, it would be ideal if the drug delivery device is a hard solid rod for easy insertion. When the drug delivery device is inside the eye, it becomes soft. In addition, if the drug delivery device can be stretched into a smaller profile, it will be implanted into a reduced incision size or hole diameter.

Therefore, surgical trauma is minimized.

[0006] From the examples given above, there is a need for ophthalmic devices which can be implanted into an opening which has a size smaller than the dimension of the ophthalmic device in its intended use conditions. Furthermore, the ideal ophthalmic device is a hard solid at the time of implantation so that it can be relatively easily implanted into the soft tissue opening. In addition, when warmed by the body temperature, the "ideal" hard solid ophthalmic device can become soft and pliable for optimal tissue compatibility.

[0007) The crystalline state of polymers is defined as one that diffracts x-rays and exhibits the first order transition known as melting (L. H. Sperling, Introduction to Physical Polymer Science, John Wiley & Sons, New York, 1992). As in small molecules, crystallinity occurs when parts of a molecule arrange themselves in a regular order or arrangement. Unlike a small molecule, polymers that crystallize in the bulk state are never totally crystalline, a consequence of their long- chain nature and the chain entanglements. Even in homopo!ymers, there will be crystalline and amorphous regions. Polymers that have crystalline regions may be referred to as crystalline or semi-crystalline polymers. The development of crystallinity depends on the structure regularity in the polymer. An increase in non-regularity of the polymer structure decreases crystallinity of the polymer and results in a lower melting temperature. The increase in non-regularity may eventually prevent crystalline regions from forming. The present invention utilizes crystalline polymers which provide a novel mechanism for deforming ophthalmic devices made from those polymers into a smaller profile than their initial size, at least in one dimension, so that they can be implanted into the eye through a relatively small incision. When the ophthalmic device is placed in the targeted location, it will return to its intended shape and dimension or adapt to a new configuration shaped by the tissue surrounding the ophthalmic device.

[0008] The present invention includes crystalline polymers that may be useful in the production of deformable lenses such as IOLs for cataract surgery, corneal inlays, and phakic refractive lenses for correcting ametropia, such as myopia, hyperopia, astigmatism, and presbyopia. The present invention also includes the use of crystalline polymers in ophthalmic devices which are not lens related. Such non-lens related devices may include, but are not limited to, ocular drug delivery devices, and implants for reducing intraocular pressure in glaucoma patients

[0009] Stay, in his U.S. Patent 4,731 ,079, issued Mar. 15, 1988, discloses a method of introducing and implanting an artificial intraocular lens to replace a surgically removed human crystalline lens through a small incision. The artificial lens material has a softening temperature in the range of about 0 °C. to about 42°C. The method comprises the following steps: first, heat the artificial lens to a temperature higher than its softening temperature; second, deform the artificial lens into a smaller profile at least in one dimension so that it can be implanted through small incision into the eye; third, cool down the deformed artificial lens to a temperature which is at least 5 °C, less than the softening temperature, so that the artificial lens will be frozen in the deformed configuration; fourth, implant the deformed lens into the eye through a small incision. After being warmed up by the eye temperature, the deformed lens will return to its pre-deformed shape and dimension. Stay further teaches that preferred materials include terpolymers which contain both hydrophobic and hydrophilic monomers as well as a minor amount of monomers with at least two polymerizable double bonds. These terpolymers can be hydrated due to the presence of a desirable amount of hydrophilic monomers. The plasticizer, water, in the case of the terpolymer, can lower the softening temperature of the lens material. Stay indicates that the softening temperature may correspond to the glass transition temperature (T _g ). However, Stay is silent on whether the softening temperature can be a melting temperature (T _m ). Those who are skilled in the art understand that only a crystalline polymer can have a T _m and that a crystalline polymer is typically not transparent due to the presence of the regular crystalline structure. According to Stay, one of the requirements for his invention is that the material must be highly transparent to visible light. Stay further teaches that preferred polymers for use in his invention are amorphous, without a substantial amount of crystalline polymer phase being present.

[0010] MemoryLens™, a commercially available implantable lens, is made from the terpolymer of methyl methacrylate (MMA), hydroxyethyl methacrylate (HE A), and a minor amount of crosslinker. According to Dr. William J. Fishkind, Memory Lens has a composition of MMA and HEMA such that the fully hydrated lens material contains approximately 20% water and has a refractive index of 1 ,47. At temperatures below 25°C, the copolymer is rigid and hard, while at temperatures above 25°C., the copolymer begins to soften and becomes elastic. This thermoplastic characteristic of the copolymer is a function of its glass transition temperature (T _g ). The MemoryLens is rolled when it is soft by increasing the temperature above its T _g and then hardened in a fixed and rolled configuration. This hardened, rolled lens is implanted into the eye through a small incision. Once placed inside the eye, the lens starts to become soft and relaxes to resume its pre-rolled shape. The complete shape recovery may take from hours to one day to finish. Dr. Fishkind has indicated that on the first postoperative day, the folding lines will have completely resolved. (William J. Fishkind, MD, Chapter 1 1 "ORC MemoryLens™-A thermoplastic IOL" in the book titled Foldable Intraocular Lenses by Robert G. Martin, James P. Gills, and Donald R. Sanders, SLACK Incorporated, 1993).

[0011] A punctal plug, described in US patent 6,234, 175, is formed from a material which can be deformed to a convenient shape for insertion into the punctum, frozen into that shape, and which regains its original shape after insertion and warming. The optical characteristics of a punctal plug are not relevant to its operability. Further, no optical devices which are inserted into the eye through a hole or incision, such as intraocular 'enses, are disclosed.

[0012] Ophthalmic devices made from crystalline or semi-crystalline

polymeric materials similar to those discussed herein are described in U.S. Patent 6,679,605, Zhou et al, issued January 20, 2004.

Summary

[0013] The present invention relates to an ophthalmic device suitable for implantation through an incision in the human eye (such as an ocular drug delivery device, an implant for reducing intraocular pressure, a corneal inlay, or, most preferably, an intraocular lens), or insertion into an existing orifice (such as a drug delivery device or plug), made from a composition containing a crystalline or semi-crystalline polymeric material having the following properties:

[0014] (a) a glass transition temperature (T _g ) in the range of from about

-100°C. to about 37°C;

[0015] (b) a melting temperature (T _m ) in the range of from about 0 °C, to about 37 °C; and

[0016] (c) wherein said glass transition temperature of the polymeric material is lower than said melting temperature for the composition. [0017] The present invention also relates to a method for implanting into the eye, through an incision, or into an existing orifice, an ophthalmic device made from a composition containing a crystalline or semi- crystalline polymeric material with a T _g in the range of from about - 100°C. to about 37°C, and a T _m in the range of from about 0°C. to about 37°C, comprising the steps of:

[0018] (a) warming up said ophthalmic device to or above its T _m , then deforming said ophthalmic device into a deformed shape which can be implanted through an incision or orifice where the size of said incision or oriface is smaller than said ophthal/.iic device in its intended use condition;

[0019] (b) cooling said deformed ophthalmic device to a temperature below the T _m such that said ophthalmic device remains in said deformed shape;

[0020] c) implanting said deformed ophthalmic device at a temperature below the T _m through said incision in the eye; and

[0021 ] (d) wanning up said ophthalmic device to and above its T _m by the body temperature in the eye, whereupon said ophthalmic device changes into a shape suitable for its intended use.

[0022] All percentages and ratios specified herein are "by weight" unless otherwise specified. All patents, publications and published applications listed in this application r.re incorporated by reference herein in their entirety.

Brief Description of the Drawings

[0023] FIGS. 1 - 13 are top views showing examples of lens designs which may be used in the present inventicn. [0024] FIG 14 shows a view of a drug delivery or glaucoma device which may be used in the present invention.

Detailed Description

[0025] The present invention is related to ophthalmic devices and their

compositions derived from crystalline polymeric materials having a crystalline melting temperature (T _m ) in the range of about 0°C. to about 37°C, preferably in the range of about 14°C. to about 30°C. In addition to the T _m , these crystalline polymeric materials also have a T _g (glass transition temperature) which is lower than the T _m for the given composition and is in the range from about - 100°C to about 37°C, preferably about -100°C. to about 20°C. In one embodiment, the crystalline polymeric material has a T _g from about - 100°C to about -17°C. Unlike the hydrogel materials iaught in the Stay, et al.- patent, discussed above, the T _m and T _g properties of the materials used in the present invention are not dependent on being in osmotic equilibrium in the body (i.e., T _m and T _g do not change in the presence of eye liquids). Although there are many different polymer structures which can form the desired crystalline regions, the preferred embodiments of the present invention include side chain crystalline-inducing polymers. The more preferred embodiments are the acrylic family of polymers with long side chain alkyls (more than twelve carbons) as the crystalline-inducing groups.

[0026] It is well known to whose who are skilled in the art that as the length of the side chain of an acrylic ester monomer increases, the T _g of the homopolymer decreases. For example, consider

t

CH ₂ = CH(R)-COO R' - y - where R=H or C¾; and R -alkyl groups, such as CH3-(CH2) _n -, n = 0 to 19.

[0027] When R=CH ₃ , and R ¹ is the alkyl grorp where n increases from 0 to

17, then T _g of the homopolymer of the respective monomer decreases. The trend is illustrated in Table 1. Additionally, as n increases from 1 1 (lauryl methacry!ate) to 17 (stearyl methacrylate), side chain crystallinity starts to form. For example, polystearyl methacrylate (n=17 in R') has a side chain crystalline fonnation with a T _m of about 36° C.

[0028]

TABLE 1

Physical Properties of Methacrylate Homopolymers in Literature '

Note:

1. Herman F. Mark, et al, Encyclopedia of Polymer Science and Engineering, Volume 1 , Pages 234-299, John Wiley & Sons, Inc. 1985.

[0029] The melting temperature, or T _m , is a characteristic of crystalline or semi-crystalline polymers. Melting may be observed visually in some materials, as the temperature increases when a material changes from white or opaque to hazy or transparent. Before the advent of sophisticated instrumental methods, melting temperatures were determined by viewing the melting polymer under a microscope between crossed polarizers. Dilatometry, where volume changes are measured, is another method for finding T _m . The use of a differential scanning calorimeter (DSC) is a popular method for examining the melting transition and is used for the determination of the T _m in the present invention.

Polystearyl methacrylate (SMA) is a white solid polymer at room temperature in its crystalline form. However, polystearyl methacrylate is found to be transparent when it is warmed to a temperature higher than its melting temperature and its side chain crystalline structure melts. Because polystearyl methacrylate has a T _g of about -100°C, it is an elastomer after it melts. These dual thermodynamic properties, one corresponding to T _g and another corresponding to T _m , are required for the crystalline polymers in the present invention. However, the homopolymer of stearyl methacrylate is tacky after it melts. This tackiness can be reduced by copolymerization with other monomers, such as methyl methacrylate (MMA). This tackiness can be further reduced by adding and increasing the amount of crosslinkers.

Crosslinkers (for example, EGDMA, ethylene glycol dimethacrylate) can also improve the elasticity of the crystalline polymer, and therefore increase its capability for recovery from a deformed state.

[0031] Table 2 is a summary of examples for the present invention.

[0032]

TABLE 2

Examples for Compositions and Their Properties

of the Present Invention

No. SMA % MMA % EGDMA % Refractive T _m (° C) T _g (° C) (by weight) (by weight) (by weight) ' Index (35 °

C)

1 100 0 0.0 1.470 34 -100 w

2 95 5 0.1 1.470 26

3 85 15 0.1 1.473 17

4 80 20 0.0 1.473 18

5 80 20 0.04 1.473 17

6 60 40 0.04 1.477 10 - 17

7 50 50 0.04 1.480 Note ⁽⁴⁾ 17

NOTES

1.

2.

3.

ben

4.

Examples of polymeric materials which may be used in the ophthalmic devices of the present invention include polymers, homopolymers, cross-linked polymers and copolymers of silicones, acrylic esters, polyurethane, hydrocarbon polymers, and combinations thereof. Specific materials include, for example, acrylic esters, copolymers of long chain methacrylates with short chain methacrylates (such as copolymers of polystearylmethacrylate with

polymethylmethacrylate), and side-chain crystalizible polymers which comprise an acrylic ester of the formula:

[0034] wherein X is H or a Ci - C6 alkyl, and R is a linear C 10-C26 alkyl.

[0035] One of the applications for the present invention is to provide an

alternative and superior method for implanting an IOL of various designs through a small incision. The IOL can be phakic or aphakic and it may be located in the posterior chamber of the eye or in the anterior chamber of the eye, or within the cornea, or a combination of them. Samples for the IOL design of t ie present invention are illustrated in, but not limited to, FIGS. 1 -14.

[0036] Of particular interest is the full size lens, such as the one in FIG. 5. A full size lens has a diameter in the range from about 8 to about 1 1 mm and a central lens thickness in the range from about 1 to about 5 mm. The present invention can allow such a full size lens to be implanted through a small incision. Because the IOL nearly fills the whole capsular bag, it may be possible that such a full size lens can inhibit secondary cataract formation. The present invention also allows such a full size lens to support the capsule. The support reduces the risk for physicians choosing to open a capsulcrhexsis, or opening in the capsular bag, on both the anterior and posterior surfaces using manual or laser techniques such as femtosecond laser capsulotomy (see Friedman, N. et al, Femtosecond Lase r Capsulotomy, J Cataract Refract Surg 201 1 , 37: 1 189-1 198, foi one description of this technique). This is done to prevent less of vision due to secondary capsular opacification.

[0037] The present invention also allows a phakic lens to be designed with larger dimensions. Increased diameter of the clear aperture of the phakic lens optic may benefit visual quality and reduce dysphotopsias such as glare, halos, and ghost images. The dimensions of the optic have been limited by the widely practiced use of the smallest possible incision size for lens implantation. The present invention will allow a phakic lens with an optic diameter between 5 and 8 mm to be deformed to a cross sectional area that may be inserted through an incision of less than 3 mm with reduced risk of trauma to tissues of the eye such as the cornea and endothelium. Some phakic lenses are designed using flexible polymers with relatively thin cross sections to better fit eyes with small anterior or posterior spaces. Such dimensional constraints could increase the risk of lens structural damage, such as tears, during insertion, Increased dimensional deformation and used of a material with crystallized side chains will reduce stress and increase durability during implantation. The lenses will become thin, soft and flexible after shape recovery.

[0038] One feature of the crystalline polymers used in the present invention is that they provide materials with a very wide range of properties, such as hardness (or softness) as measured by Durometers. Because T _g and T _m are two distinctly different thermodynamic transitions in polymer properties, it is possible to provide very soft materials by the present invention. For instance, example 1 in Table 2 has a melting point of 34°C corresponding to the crystalline structure formed by the side chain stearyl group, and a T _g of -100°C corresponding mainly to the long polymeric backbone structure. At room temperature, it is a hard white solid. However, when the copolymer is heated up to the melting temperature or higher, it becomes transparent after all crystalline side chains have melted. It also becomes very soft because the melted side chain stearyl groups function as a pla-vicizer or as if it were a "solvent". This low hardness can be a very useful property in the case of a full size lens design which may possibly accommodation for the presbyopia patients. [0039] The "fluid" property due to the melted crystalline side chain is also the driving force in the present invention for the ophthalmic device to adapt to a new configuration shaped by the surrounding tissue. On the other hand, the elasticity due to the long chain of the polymer backbone and the crosslinking is the driving force for the shape recovery of the ophthalmic devices from the deformed shape to the pre-deformed shape. This crystalline-fluid interphase change of the long side chain provides a novel mechanism for achieving the goals of the present invention.

[0040) In order to understand the way the present invention is practiced, an intraocular lens (10L) is used as an example. The IOL of the present invention is made from crystalline po!ymeric materials having the following properties:

[0041] (1) Crystalline melting temperature, T _m , in the range from about

0°C to about 37°C, preferably from at out 15°C to about 30°C.

[0042] (2) Glass transition temperature, T _g , in the range from about

-I 00°C to about 20°C, preferably from about - 100°C to about -17°C In all cases, T _g , should not be higher than room temperature.

[0043] (3) Being optically transparent at or above the T _ra . On the other hand, it is not necessary for the IOL made from the crystalline polymeric material to be transparent below the T _m . It may not be a requirement for non-lens related applications that the crystalline polymer be transparent at any given temperature. Furthermore, other additives may be added to the crystalline polymer composition as required by the specific circumstances. For example, an ultraviolet (UV) absorber may be incorporated into lenses for the protection of human eyes from damage caused by IN light exposure. Another example is that barium sulfate may be added to a non-lens device for rendering it radio-opaque. Therefore, the device can be examined by a radiological method if needed.

[0044] The method for implanting the IOL (or other ophthalmic device) of the present invention includes the following steps:

[0045] (a) Warm the IOL to a temperature at or above the T _m , then deform the IOL into a shape, such as folded, rolled, and/or stretched at the same tune, w ich can be implanted through a small incision into the eye. The ideal size for the incision is from about 2 to about 4 nun,

[0046] (b) Cool down the deformed IOL to a temperature below the T _m while the deforming force, such as folding, rolling, clamping, and/or stretching, etc., is still applied to the IOL. After removing the deforming force, the cooled IOL will remain in its deformed shape.

[0047] (c) Implant the deformed lens at a temperature below the T _m

through a small incision into the eye so that the lens remains in the solid deformed form and that it is relatively easy to insert into the soft tissue opening.

[0048] (d) When warmed up to and abov; the T _m , by the body temperature of the eye, the deformed IOL will return to its pre-deformed shape, providing the desirable optical power ¾nd resolution for the patient.

[0049] Example 1 - Lens Preparation

[0050] To a round-bottomed flask, equipped with a magnetic stir bar, is added a mixture of 4.75 grams of SMA, 0.25 gram of MMA, 5 microliters of ethylene glycol dimethacrylate, and 0.01 gram of benzoyl peroxide. The flask is purged with nitrogen gas for about 2 minutes and subsequently maintained under positive nitrogen atmosphere. The reaction mixture is then heated to about 1 10°C while stirring. After approximately 5 minutes, evolving of gas is observed, indicating decomposition of the benzoyl peroxide initiator to form benzoyloxy radicals initiating the polymerization reaction. After approximately 5 minutes from when the initial gas evolution is first observed, the reaction mixture becomes obviously viscous, indicating the polymerization and crosslinking reaction has occurred. Before the reaction mixture becomes too viscous to be poured out from the flask, a small amount of the mixture is taken out with a spatula and is transferred into an IOL mold. The mo d is then closed and is placed into a preheated oven at 1 10°C for 16 !iours. After the mold is taken out from the oven and cools down to : oom temperature, the mold is placed in a refrigerator for about 2 ho -js. The mold is then opened. A white or translucent solid IOL is carefjlly removed from the mold.

[0051] The IOL prepared from above procedure is placed in warm water

(37°C, for example), and the IOL gradually changes from the white or translucent solid to a transparent soft lens. This soft lens can be stretched to reduce the intersectional area in the warm water bath. The stretched IOL is then removed from the warm water bath and allowed to cool down to the room temperature. The stretched IOL retains its stretched shape after about 3 minutes. The stretched IOL gradually changes from transparent to translucent and then to white hard solid. If an ice water bath is used instead of room temperature air, this "freezing" process can be completed in about 1 minute.

[0052] When the stretched IOL is warmed again in a 37°C saline solution or water bath, it returns to its pre-stretch^d shape in about 1 minute. The recovered lens is transparent and soft ¾s long as the temperature is maintained at 37°C or higher. Other compositions in Table 2 are prepared in a similar manner. When a UV absorber is used, it can be added to the initial reaction mixture before the heating step. In addition, ice water is preferably used for these compositions with the T _m less than 20°C for the freezing step. [0053] Example 2 - Rod Preparation

[0054] A mixture of 5 grams of stearyl methacrylate and 0.01 gram of benzoyl peroxide is wanned to about 40°C so thai it becomes a homogenous solution. The mixture is degassed and refilled with nitrogen. After the mixture is transferred into a polypropylene tube with an internal diameter of about 1mm and with one end pre-sealed by heating, the open end is also sealed by heating. Hie sealed tube is about 2 inches long and is placed in an oven at 1 10°C for 16 hours. At the end of the reaction, the oven is cooled down to r >om temperature. Then both ends of the sealed tube are cut off. The w ^' te solid rod inside the tube can be pushed out from the tube with a metal wire. The white solid rod prepared from above procedure can b warmed up in a water bath (45°C, for example). It becomes transparent and soft almost instantly. The soft rod is stretched in the water I ath until the diameter of the rod becomes about 0.3 mm. The stretched rod is then lifted from the warm water bath to the room temperature air. It becomes solid in about 1 minute and retains its stretched shape as long as the temperature remains below its melting temperature. When the stretched rod is warmed up in a saline solution, such as 37°C, it becomes soft and its diameter changes back to 1 mm in about 1 minute.