Title:  Intraocular lens containing releasable medication

United States Patent:  6,713,080

Issued:  March 30, 2004

Inventors:  Aiache; Jean-Marc (Clermont-Ferrand, FR); Serpin; Gilbert (Clermont-Ferrand, FR); El Meski; Said (Beaumont, FR); Tourrette; Philippe (Clavette, FR)

Assignee:  Ioltechnologie-Production (La Rochelle, FR)

Appl. No.:  332120

Filed:  June 14, 1999

Abstract

The present invention relates to an intra-ocular lens that is made from hydrophilic polymer. An effective amount of medicine is dispersed in the mass of the of the polymer and when implanted in the eye of a subject, the lens releases the medicine into the intra-ocular tissues so that the medicine is in the vicinity of the site where action is needed.

SUMMARY OF THE INVENTION

According to an aspect of the invention, a lens is provided for implantation in the eye of a subject, and notably to be substituted for a defective crystalline lens, after extraction, during a surgical operation, which lens is made from a polymer having a predetermined water content, the polymer containing, dispersed in its mass, an effective quantity of a medicated product with appropriate effects, in particular at least partial inhibition of postoperative reactions of the eye, the association of the polymer and the dispersed medicated product being adapted to release the product progressively into the aqueous humor and intraocular tissues.

Because the polymers from which the lenses are made are hydrophilic, the medicated product is released progressively into the aqueous humor and is therefore in immediate range of the sites where its action is required.

In the present context a hydrophilic polymer is a polymer that is able to contain water to enable release of the active products into the aqueous humor. The water content (hydrophilic rate) must be at least 0.20% by weight and preferably at least 0.25% by weight.

Other prior art

The article "Drug Uptake and Release by an Hydrogel Intraocular Lens and Human Crystalline Lens" (Heyrman T. P. et al.), published in Journal of Cataract & Refractive Surgery, vol. 15, No. 2, 1989, discusses the behavior of polymethyl methacrylate or PMMA IOLs compared to the eyes of living beings (rabbits and humans), vis-a-vis medications, in particular anti-inflammatory medications, used for operative and postoperative treatment in cataract surgery. Experiments in vitro and in vivo (on rabbits only) show that the hydrogel absorbs the medications in quantities and at a rate very similar to those for the crystalline lens and that release into the aqueous (and vitreous) humor occurs under similar conditions. The authors conclude that the IOLs studied cannot function as significant reserves of medications in the eye.

The article "Drug Interaction with Intraocular Lenses of Different Materials" (J. M. Chapman et al.) published in Journal of Cataract & Refractive Surgery, vol. 18, No. 5 (1992), complements earlier studies on the interaction of medications with PMMA and polyhydroxyethyl methacrylate (or polyHEMA) IOLs (including the studies reported in the article mentioned previously), by considering other materials and other medications. The article concludes that IOLs cannot deliver sufficient quantities of medications into the eye to modify significantly the kinetics of medications applied topically, sub-conjunctively or intravenously and replace conventional treatments.

The communication "Use of Methyl Polymethacrylate (PMMA) as a Drug Support" EI Meski, Beyssac and Aiache; Proc. 1st World Meeting APGI/APV, Budapest 9/11 May 1995, pages 323-324, teaches a method of incorporating a medication into PMMA including drying of the polymer, absorption of a solution of medication in a water/ethanol support comprising 57% by weight of ethanol and final drying (5 days at 110^oC.) to evacuate the support.

The step from the teaching of the above communication to the method as defined hereinabove has necessitated, on the one hand, the original concept of using the material of a hard intraocular lens as a reservoir of a medicated product that can be released into the aqueous humor and the surrounding ocular tissues and, on the other hand, the unexpected discovery that the polymer treated in accordance with the teachings of the aforementioned communication could provide a lens optically and surgically suited to long-term substitution for the crystalline lens.

The above communication notes that diffusion of the support into the polymer causes profound changes to the structure of the implant, namely a change from the hard vitreous state to an elastic state analogous to rubber during impregnation, followed by a return to the vitreous state on evaporating the support.

Furthermore, the step from the treatment of a material for hard lenses to that of a material for soft lenses, implanted in a swollen state, involved major unknowns because of the different behaviors of the polymers relative to the solvents likely to constitute the supports and the different rates of diffusion and release specific to these types of polymers.

Our work has shown that for the invention to be effective it is necessary to adapt some operations of the method to the nature of the polymer used for the lens.

Thus, in the case of a polymer for hard lenses, it is necessary to carry out the impregnation at a high temperature on a blank that is then configured or machined into an intraocular lens, in order to have an optical part without surface imperfections and haptic parts that have not been rendered fragile.

In the case of a polymer for soft lenses, it is necessary to sterilize the conformed lens in an isotonic solution containing a chosen concentration of medicated product.

This sterilization process can bring about the impregnation. Alternatively, impregnation follows or precedes sterilization. The concentration of the medicated product is chosen according to the required charge of medicated product in the lens and the reciprocal properties of the polymer and the medicated product.

Other features and advantages of the invention will emerge further from the following description, which is associated with examples and refers to the accompanying drawing.

EXAMPLES OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The first experiments to develop the invention concerned intraocular lenses made from a polymer for hard lenses, namely PMMA. Impregnation of intraocular lenses in accordance with the principles set out in the aforementioned communication of El Meski, Beyssac and Aiache, in their final conformation, caused fragilization of the haptic loops and defects of the dioptric surfaces, as a result of which the lenses were of insufficient quality.

Example 1

Preparation of Hard PMMA Lenses

Disks or semi-finished PMMA blanks were subjected to the following treatment:

Drying of the blanks in an oven at 110^oC. for 24 hours to remove internal water;

Immersion, at a high temperature, for 24 hours in a solution of a water/ethanol support containing 57% by weight ethanol, saturated with diclofenac, contained in an opaque container, and maintained at 50^oC.;

Rinsing in a 50% water/alcohol mixture;

Drying at 110^oC. for 5 days;

Lathe cutting of the blanks into intraocular lenses of the desired configuration;

Polishing the dioptric surfaces; and

Cleaning and sterilization.

Example 2

Preparation of Lenses Impregnated with Indomethacin

PMMA blanks were subjected to the same treatment as in Example 1 except that the water/ethanol support containing 57% ethanol was saturated with indomethacin. Otherwise, the operations were exactly the same.

Various experiments, effected by in vitro release on treated but not conformed IOL blanks showed that the doses of the medicated product contained in the blanks were of the required order of magnitude and that the rate of release into an isotonic solution (comparable in behavior to the aqueous humor) should assure suitable periods of activity.

Example 3

Kinetics of Release in the Rabbit

Three PMMA intraocular lenses impregnated with indomethacin as in Example 2 were each implanted as a substitute for the crystalline lens in one eye of a rabbit, the opposite eye serving as a control.

Samples of the aqueous humor were taken from the treated eyes at DO (before implantation), D7, D14, D21 and D28, i.e. five samples per rabbit.

The indomethacin was measured by high-performance liquid chromatography.

Clinical examination showed that the inflammatory reactions had disappeared by the tenth day from implantation and that the treated eye was identical to the control eye.

In practice, the measured levels of indomethacin in the aqueous humor samples did not yield quantifiable results; only samples 3 and 4 from one rabbit (second and third weeks) contained significant traces, in the order of 0.25 .mu.g/ml.

It can therefore be concluded that the clinical results are satisfactory and that the doses released or absorbed after release are of the same order as the quantifiable limit. This example emphasizes the benefit of localizing the distribution of the medicated product to the immediate vicinity of the action sites, in order to limit the doses of product delivered into the eye and to avoid the product having any unwanted action in other parts of the body.

The following examples concern soft intraocular lenses, in particular lenses made of polyHEMA (polyhydroxyethyl methacrylate).

Example 4

Impregnation of PolyHEMA

A polyHEMA intraocular lens (containing 38% by weight of water), ready for implantation, was removed from its shipping container, weighed and dried in an oven at 50^oC. for 75 minutes. Its mass was only 62% of its original mass, showing that substantially all of the water content had been removed.

The lens was then immersed in a water/ethanol support containing 57% by weight of ethanol, saturated with indomethacin and maintained at 50^oC. After 15 minutes immersion the mass of the lens was 115% of the original mass (185% of the mass in the dry state); after 35 minutes it was 130% of the original mass (200% of the mass in the dry state); after 45 minutes it was 150% of the original mass (240% of the mass in the dry state).

Similar experiments using lenses dried for shorter periods showed that the percentage swelling in the water/ethanol support saturated with medicated product depended on the duration and the rate of drying. In this way it was possible to adjust the quantity of medicated product fixed in the lens.

Example 5

Preparation for Implantation

A polyHEMA intraocular lens impregnated as described in Example 4 was washed in a 0.9% NaCl buffer solution (isotonic solution) having a pH of 7.0 and saturated with indomethacin and then placed in an individual shipping container containing the aforementioned buffer solution saturated with indomethacin. The container containing the lens was sterilized in an autoclave at 120^oC. for 30 minutes.

Inspection of the lenses at the end of preparation showed that they had not been degraded; they nevertheless had a yellowish tint proving the presence of indomethacin.

Example 6

Kinetics of Release in the Rabbit

A lens prepared as in Example 5 was implanted in the anterior chamber of the right eye of a rabbit. Samples of aqueous humor (approximately 150 .mu.l) and plasma (approximately 2 ml) were taken at random intervals. The indomethacin in the samples was measured by high-performance liquid chromatography (HPLC).

The graph in the single figure of drawing of the present application shows the results of the measurements.

Note that indomethacin was detectable up to the twentieth day. The concentration of indomethacin in the aqueous humor shows a main peak (approximately 0.25 .mu.g/ml) toward the third day and a slight secondary peak (approximately 0.11 .mu.g/ml) toward the seventh day. The concentration in the plasma increased progressively up to the seventh day (approximately 0.9 .mu.g/ml) and then fell at a regular rate until the twentieth day.

Clinical observations showed that the lenses were well tolerated and that the inflammatory reactions disappeared at least as quickly as in Example 3.

Analogous experiments were undertaken with soft intraocular lenses made from other polymers, such as "acrylic polymer". In the present context, "acrylic polymer" means the polymers called this in the field of intraocular lenses, such as a mix of methacrylate and methylmethacrylate.

Even silicone polymers are feasible. By "silicone polymers" it is meant polymers such as conventionally used in the intraocular field and having a minimum water content or hydrophilic rate of at least 0.20%, for example. To this end, the silicone-based polymer is subjected to physical-chemical transformation to shorten the chains so that the polymer in liquid form can be impregnated with the medicated product. Obviously the polymer when so impregnated must be conformed into an intraocular lens.

It was found that, after appropriate drying to remove internal water, impregnation could be carried out during sterilization, the lenses being enclosed in shipping containers containing, as a support, an isotonic solution buffered to pH 7.2 and having a chosen concentration of medicated product.

Sterilization was then performed in an autoclave at 120^oC. for 25 minutes.

Example 7

The objective of this example and the following examples was to determine conditions under which effective quantities of the medication could be introduced into soft, polyHEMA IOLs.

Initially, polyHEMA soft IOLs were impregnated by immersing them in a solution saturated with diclofenac (1.8 mg/ml, prepared by dissolving sodium diclofenac in a 0.9% solution of NaCl), at room temperature for 72 hours, carefully rinsed and then released into 1 ml of a 0.9% NaCl solution. After 6 hours, 24 hours and 96 hours, the diclofenac was measured in the release solution by HPLC, after which the IOL was rinsed and, for the intermediate durations, left to release in new solution. The results are shown in the following table. It is understood that the released quantities correspond to the quantities previously absorbed and fixed in the IOLs

Released quantities in Cumulative or total released

Example 8

The experiment of Example 7 was repeated leaving the IOLs in the saturated solution for 7 days instead of 3. The quantities released were checked after 6 hours and 24 hours. The results are shown in the following table.

Released quantities in Cumulative or total released

It was found that extending the period of impregnation in the saturated solution from 3 days to 7 days had practically no effect on the quantities released, which means that after 72 hours at room temperature the IOL was practically saturated.

The following experiments were intended to determine more precisely the kinetics of release of diclofenac (in vitro experiments).

As previously, the quantities released were measured by sampling the release medium (0.9% neutral NaCl solution) at intervals for measurement and renewing it for a new interval. The samples were taken after 6 hours and 24 hours and then every 24 hours for 14 days in total To approximate the actual (i.e. in vivo) conditions of use more closely, release was effected at 35^oC.

The IOLs were impregnated by two different methods. For a first experiment, the IOLs were placed in the solution saturated with diclofenac after which the combination was sterilized at 122^oC. for 30 minutes. A second experiment was carried out without sterilization, the IOLs remaining in the diclofenac solution for 24 hours.

The quantities released were substantially the same, to within +10%, and are set out in the table below in hours (H), days (D) and .mu.g/ml.

It was noted that the quantity of diclofenac at saturation was practically independent of the impregnation temperature, saturation at room temperature being achieved in less than three days, as shown by the previous experiments. However, saturation was achieved much faster at a higher temperature, which permits simultaneous sterilization and impregnation. Finally, confirming the in vivo experiments previously described, therapeutic coverage extended over at least 15 days, satisfactorily preventing postoperative inflammation.

Example 9

This example involved two sets of five hydrophilic acrylic IOLs. For fixation of the diclofenac, each IOL was placed in a 1.5 mg/ml diclofenac solution and autoclaved for one cycle (120^oC. for 30 minutes). To determine quantities fixed during autoclaving, quantities released from the IOLs were measured by successively heating the implants in a double boiler at 97^oC., cooling, then leaving them at ambient temperature for a prolonged period, and then repeating this procedure. In each series, Ferrylab stirring was used either prior to or subsequent to the first rest period at ambient temperature. The results are given in the following two tables, respectively for the first and second sets of five IOLs.

It follows from the total quantities released that the average amount of diclofenac absorbed by each IOL of the series was 37.29 .mu.g.

It follows from the total quantities released that the average amount of diclofenac absorbed by each IOL of this series was 39.46 .mu.g.

Example 10

This example involved impregnation of the IOLs both during and after sterilization to evaluate the quantities of the medicated product which were absorbed by the implants.

Each of three hydrophilic acrylic implants of the type used in Example 9 was first introduced into the container with a 0.9% NaCl solution containing 1.5 mg/ml diclofenac solution. The container was then autoclaved at 122^oC. for 30 minutes. After autoclaving, the IOLs were left in their impregnation solution for 10 days at ambient temperature. The procedure described in Example 9 was used to release the absorbed quantities of the diclofenac from the IOLs. The amounts released were respectively 83.57 .mu.g, 101.66 .mu.g, 84.16 .mu.g or an average of 89.79 .mu.g per implant. These results were over twice as great as those obtained in Example 9 (average about 38 .mu.g per implant), which involved combining the sterilizing and impregnation steps but which was not followed by extended residence in the impregnation solution.

Example 11

This series of tests was conducted on five hydrophilic acrylic IOLs. The same as those used in Examples 7-10. Each IOL was immersed in a 5 ml of a 1.5 mg/ml diclofenac solution in water sterile for injection for ten days and at ambient temperature without autoclaving prior or after immersion. A simplified procedure for releasing the absorbed quantities of diclofenac was employed which only used double boilers and rest periods but no stirring in a Ferrylab.

On average, each implant has absorbed 100.73 .mu.g of diclofenac.

It is noted that relatively large amounts (in excess of 90 .mu.g) of the active ingredient were absorbed either by autoclaving (Example 10) or by immersion at room temperature (present example). The high level of absorption through autoclaving (Example 10) may be explained by the expansion of the polymeric structure by heating, thereby favoring the penetration of the medicated product (here diclofenac) inside the mesh of the polymeric network but high quantities absorbed by mere immersion at room temperature of the present example was unexpected.

Example 12

It then remained to be shown how quantities of the active ingredient absorbed could be maintained at a desired high level, in excess of 90 .mu.g and preferably in excess of about 100 .mu.g, until implantation by the surgeon.

This example included tests on 21 IOLs to ascertain the time it takes for the amount of diclofenac absorbed by the IOL to reach its equilibrium. Each IOL was immersed in 5 ml of 1.5 mg/ml diclofenac solution in deionized water and then sterilized as is conventional, namely at 120^oC. for a period of 30 minutes. The sterilized IOLs were then allowed to cool and left in the impregnation solution at room temperature for respective periods of 10 days, 20 days, 35 days, 41 days, 50 days and 65 days. At the end of each of these periods, three IOLs were removed and the quantity of diclofenac was then measured by forced release comprising cycles in a double boiler at 97^oC. followed by rest periods until the diclofenac was entirely released from the IOLs.

The amounts of diclofenac released and corresponding to the amounts absorbed for the respective periods are expressed in .mu.g. These tests show that a substantially equilibrium state with high level of absorbed active ingredient could be achieved by immersion residence of a minimum of 20 days. These results are set out in the following table.

t is noted that a level of about 90 .mu.g is achieved after 10 days, and about 100 .mu.g after 20 days and thereafter (except for the dip registered at 35 days) remains substantially constant at a level slightly over 100 .mu.g.

This example establishes that by maintaining the IOLs in the sterilization liquid with the active ingredient for periods of at least 10 days and preferably 20 days equilibrium of the amounts of the active ingredient may be achieved to ensure predetermined, high quantities of the active ingredient at the time of implantation

Example 13

In all the preceding examples the diclofenac was used at concentrations of 1.8 mg/ml or 1.5 mg/ml that is at or only slightly below the saturation level. To avoid the problems attendant to the use of saturated or near saturated solutions, namely instability and risk of precipitation into crystals, other tests have been conducted at lower levels of concentration, namely 0.9 mg/ml, 0.45 mg/ml and 0.225 mg/ml.

In these tests, hydrophilic acrylic IOLs sold by loltech, La Rochelle, France, under the trademark Stabibag were first sterilized in their sealed containers in a 0.9% NaCl solution, in accordance with the standard sterilization procedure used for conventional IOLs. The solution contained no active ingredient of any kind.

After sterilization at 121^oC. for 30 minutes the containers were opened and the IOLs transferred to other containers which had previously been filled with a 0.9% NaCl solution including respectively 0.9 mg/ml, 0.45 mg/ml and 0.225 mg/ml of diclofenac. The IOLs remained immersed in the impregnation solution for 4 days in each case. Thereafter the absorbed quantities of diclofenac were driven out of the IOLs in double boilers at 97^oC. as described above. The quantities fixed were substantially the same as found in Example 7 above, establishing that sterilization prior to impregnation does not negatively effect the quantities diclofenac absorbed by the implant during impregnation. These results are as follows:

70 .mu.g per IOL in the 0.225 mg/ml diclofenac solution after 4 days of immersion;

148 .mu.g per IOL in the 0.45 mg/ml diclofenac solution after 4 days of immersion; and

276 .mu.g per IOL in the 0.90 mg/ml diclofenac solution after 4 days of immersion.

In a second series of tests conducted with an impregnation solution of 0.9% NaCl with 0.9 mg/ml diclofenac under the same conditions as in the first series, except that the residence in the impregnation solution was 49 days. The resulting average quantity of diclofenac fixed by the IOLs was 502 .mu.g diclofenac per implant.

Example 14

A test was carried out on three rabbits which were implanted with hydrophilic acrylic IOLs impregnated by autoclaving in a 1.5 mg/ml diclofenac solution at 120^oC. for 30 minutes as described in Example 9 above. The object of this test was to determine the anti-inflammatory effect of diclofenac after a cataract operation. After extraction, the crystalline lens in each eye, the left eye was fitted with an impregnated IOL according to the invention and the right eye with the same kind of IOL with no medicated product therein. The eyes of the rabbit were examined by an operator on day one and microscopically by an ophtalmologist on day 7 and day 14 after the operation. The observations are set out in the following table.

In summary, the preceding table shows that following the operation, the left eye appears normal without apparent inflammatory whereas the right eye is half closed, red and has a flow of inflammatory liquid. At the microscopic examinations on days 7 and day 14, the treated eye shows signs of inflammation in a slight fibrotic deposit on the optic and haptic and some synechies on the right eye of much greater signs of inflammation with systematic fibrotic deposits and frequent posterior synechies. This test establishes a real anti-inflammatory effect of an implant with releasable quantities of diclofenac in the mass of the IOL.

Accordingly, in addition to nonsteroid anti-inflammatory preparations such as diclofenac and indomethacin, tests were carried out with steroid anti-inflammatory products such as dexamethasone.

Impregnation is also envisaged for other medicated products such as antibiotics, antimytotics and other anti-infection products usable to treat ocular or other tissues.

The medicated product can include any necessary active ingredient given the condition of the subject at the time of the operation.

Generally speaking, the experiments showed that the nature of the medicated product had practically no influence on impregnation provided that it was sufficiently soluble in a support able to diffuse into the mass of the polymer.

However, the treatment, in particular sterilization, of the lenses or blanks must obviously not destroy or denature the medicated products and must be adapted if these products are fragile.

In addition to the high temperatures used for impregnation, low temperatures are feasible if, for reasons of stability of the medication (dexamethasone, mitomycin or certain enzymes), impregnation at temperatures below room temperature (for example from 0 to 10^oC.) is necessary to preserve the activity of the products.

Impregnation after sterilization is also possible if the sterile implant is brought into contact with the medicated solution only a few minutes, or even a few hours, before implantation, this being true for polyHEMA or acrylic polymer implants with a high hydration power. Sterilization is thereby effected before impregnation which will prevent denaturing the medicated product, especially those likely to become denatured at high temperature.

Finally, the solvents that could be used as impregnation supports include, over and above those described in the examples and the experiments referred to above, isopropyl alcohol and acetonitrile in the group of organic solvents or complex saline solutions in the group of aqueous solvents, such as intraocular irrigation solutions and in particular BSS.

It will be understood that the foregoing description and examples are not limitative of the invention, the scope and spirit of which are defined in the appended claims.

Claim 1 of 40 Claims

What is claimed is:

1. An intraocular lens comprising an optic part and a haptic part, said intraocular lens being comprised of a hydrophilic polymer having a predetermined water content for implantation in an eye, an effective quantity of a medicated product for at least partial inhibition of postoperative reactions of the eye being dispersed in the mass of the hydrophilic polymer of the intraocular lens, the association of the hydrophilic polymer and the dispersed medicated product being adapted to release the product progressively into the aqueous humor.

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