GB2204238A - Viscoelastic fluid for opthalmic surgery - Google Patents

Abstract

This invention relates to an improved viscoelastic vitreous substitute for use in ophthalmic surgery which consists of a mixture of hydroxypropylmethyl cellulose and polyethylene oxide in selected concentrations not to exceed approximately 2 % and 200 ppm, respectively, contained in a physiologic balanced salt solution. It also encompasses the novel method of protecting and lubricating the corneal tissues during surgery with uses of different concentrations of the same solution introduced simultaneously to protect the inner cornea while periodically irrigating the outer cornea, all without obscuring the surgeon's view of the site.

Description

VISCOELASTIC FLUID FOR OPHTHALMIC SURGERY AND METHOD OF USING SAME The present invention relates to an improved viscoelastic formulation for ophthalmic surgery.

Embodiments of the invention when used in dilute form as a topical solution in place of balanced salt solution to keep the corneal surfaces moist have been found to last up to ten times as long in the eye before having to be renewed. Embodiments of the invention when used in a different concentration have proven to be equally as good if not better than sodium hyaluronate for use as a protective agent for the inner endothelial corneal surface and other delicate inner eye structures during ophthalmic surgery and are considerably less expensive. The invention also relates to methods of irrigating and protecting the corneal tissues during ophthalmic surgery.A method according to the invention encompasses the steps of using two different yet compatible solutions together during ophthalmic surgery so as simultaneously to protect the cornea and irrigate it without obscuring the surgeon's view of the site in any way.

There are a number of surgical procedures performed on the eyes by skilled ophthalmic surgeons. Among these are cataract surgery, vitreo-retinal surgery and radial keratotomy to reduce myopia. In all of these surgical procedures, except for radial keratotomy in which the corneal tissue is not penetrated, the recommended practice is to use an intraocular viscoelastic fluid for protecting the inner endothelial corneal surface and the delicate inner eye structures.

In addition, the outer epithelial surface of the cornea must be lubricated continuously with some type of moisturizing agent to keep it from drying out under the heat generated by the operating microscope light.

Methylcellulose has a long history of safe and effective use for ophthalmic applications. In 1945, Dr. Kenneth C. Swan studied the effects of methylcellulose on the ocular tissues of rabbit eyes.

He suggested its use as a vehicle for ophthalmic drugs, to treat keratoconjunctivitis sicca and as an embollient. Then in 1959, Flemming, Merrill and Girard reported on further studies of methylcellulose in relation to irritation, hypersensitivity and its outflow from the anterior chamber of the rabbit eye.

The first reported use of methylcellulose as an intraocular lens coating serving to protect the corneal endothelium in rabbits was made by Drs. Kaufman and Katz in 1976. In the following year, Dr. Paul Fechner reported upon the first human clinical use of methylcellulose to coat an intraocular lens prior to implantation.

Then, in November of 1982, Dr. Danielle Aron-Rosa reported using methylcellulose in extracapsular surgery instead of high molecular weight sodium hyaluronate extracted from rooster combs which is very expensive.

Shortly thereafter, Dr. Fechner amplified upon his earlier findings describing the use of methylcellulose as a viscous cushioning material in ophthalmic surgery.

Addition work confirming these earlier results has been conducted by Dr. Scott M. Mac Rae who compared the efficacy and toxicity of sodium hyaluronate, methylcellulose and chrondroitin sulphate, all three of which are used as protective substances suitable for use in ophthalmic surgery. Finally, Drs. Smith and Lindstrom evaluated the safety and efficacy of 2% methylcellulose in cat and monkey implant surgery with favourable results.

Despite the high cost of viscoelastic products based upon sodium hyaluronate, all commercially available ones in common use have it as the sole or at least principal ingredient. Some manufacturers of viscoelastic materials are believed to be engaged in experimentation with a bioengineered form of sodium hyaluronate but so far it appears that efforts at producing it with a sufficiently high molecular weight have been only marginally successful. A polyacrylamide material is evidently being tested as is a material having hydroxypropyl methylcellulose as its basic ingredient.

On the other hand, as far as topical solutions for use in surgery to lubricate the corneal epithelium and protect them from the heat generated by the operating microscope, to applicants' knowledge the only product used at the present time is a balanced salt solution which must be administered as often as every 30 to 45 seconds by an assisting surgeon or scrub nurse.

As already noted, the use of methylcellulose derivatives as protective cushioning materials to protect the inner eye structures during ophthalmic surgery is old and well known. On the other hand, use of methylcellulose as one ingredient of a topical surgical solution which, in a more dilute form, is used to keep the corneal tissues moist as an adjunct to surgery is, so far as applicants' are aware, heretofore unknown in the art although it is, of course, used as an ingredient in so-called "artificial tears" for treating dry eyes and as a component of contact lens solutions.

The closest and most pertinent prior art known to the applicants is contained in two U.S. Patents, specifically US-PS 4 500 538 issued February 19, 1985 to Otto W. Woltersdorf under the title of "Benzothiazolesulfonamide Derivatives for the Topical Treatment of Elevated Intraocular Pressure" and US-PS 4 287 175 issued September 1, 1981 to Irving Katz for "Contact Lens Wetting Agents", both of the aforementioned patents being assigned to Merck & Co., Inc. The Katz Patent teaches the use of hydroxypropylmethyl cellulose or polyethylene oxide among other polymeric viscosity building agents as a solid water soluble insert as a wetting agent for contact lens wearers or so-called "artificial tears".

These wetting agents are, however, used in solid form and, as such, are totally unsuitable for use in protectin the delicate epithelial cells in ophthalmic surgery. Moreover, there is no suggestion that they be used together or that any useful result whatsoever would be achieved by so doing. As a matter of fact, the elastic properties of the two in combination or, for that matter either one alone, is not a factor in their use as wetting agents.

The Woltersdorf Patent also mentions the use of hydroxypropylmethyl cellulose and polyethylene oxide as solid water soluble carriers for the active medicament of the invention, namely, the carbonates of 6 or 5-hydroxy-2-benzothiazolesulfonamide for use in the reduction of elevated intaocular pressure of the type often associated with flaucoma. Here again, these high molecular weight substances are used merely as a base for the active ingredient when used as a solid insert as opposed to a solution administered in the form of drops. There is no mention of them being used together nor is their elastic property of any consequence in this application. Most significant, however, is that the formulation of the Woltersdorf Patent would be unsuitable for use as a viscoelastic coating to protect the delicate inner eye surfaces during ophthalmic surgery or, for that matter, as a topical moisturizing agent to be used during such surgery as a long-lasting moisturizing agent.

According to the invention, there is provided a viscoelastic aqueous/vitreous substitute for ophthalmic surgery which comprises a solution containing at least approximately 1% hydroxypropylmethyl cellulose and at least approximately 100 ppm polyethylene oxide in a physiologic balanced salt solution.

According to the invention, there is also provided a method of irrigating and protecting the corneal tissues during ophthalmic surgery which comprises the steps of covering the inner cornea with a physiologic saline solution containing approximately 2 í hydroxyprophymethyl cellulose and approximately 10 ppm polyethylene oxide while simultaneously periodically wetting the outer cornea with a compatible physiologic saline solution containing approximately half the hydroxypropylmethyl cellulose and approximately twice the polyethylene oxide.

Viscoelastic solutions embodying the invention and methods according to the invention will now be more specifically described.

The anterior chamber of the eye is filled with circulating aqueous fluid, whereas its posterior chamber is filled with vitreous fluid. The endothelial cell layer of the cornea is easily damaged and, once lost, these cells do not regenerate. The surgical procedures used in cataract surgery, corneal transplants and other types of ophthalmic surgery are likely to result in damage to these delicate cells unless measures are taken to protect them in the manner in which the aqueous fluid does naturally.

Of the several prior art substances that have been developed as substitutes for aqueous and vitreous both as a protective layer covering the endothelial cells and as a coating on the surgical instruments and implanted material, undoubtedly the most widely used is sodium hyaluronate extracted from rooster combs, mixtures thereof or bioengineered forms of the naturally-occurring substance. Once the surgical procedure is conpleted, the remaining vitreous/aqueous substitute is aspirated from the site using a syringe while what is left over is merely resorbed by the body in time without ill effect.

The main problem with hualuronate-based products is their cost which at the present time runs around $70 or so for less than a cubic centimetre of material. While attempts have been made to use various methylcellulose derivatives as less expensive viscoelastic substitutes, they have not been well accepted nor do they work as well as hyaluronate.

It has now been found that a vastly improved material having greatly improved elasticity at least equivalent to sodium hyaluronate, but at a fraction of its cost, can be made by the simple, yet unobvious, expedient of combining the relatively non-elastic hydroxypropylmethyl cellulose with a high viscosity thixotropic elasticizer, specifically saline solution.

Hydroxypropylmethyl cellulose is clear, non-toxic and quite viscous; however, it is also essentially non-elastic. It has now been found that, quite unexpectedly, the addition of polyethylene oxide which is a thixotropic material having a nominal molecular weight of 4 million greatly improves the elasticity of the mixture and makes it comparable, if not superior, to sodium hyaluronate for use as a viscoelastic material in ophthalmic surgery.

Another problem encountered in ophthalmic surgery is that of keeping the external tissues of the eye moist under the drying effect of the operating microscope.

As previously noted, this is generally handled on a more-or-less continuous basis by irrigating the external corneal tissues with a balanced salt solution, sometimes as often as twice a minute. Unexpectedly, it has been discovered that a carefully modified version of the mixture used as the intraocular viscoelastic material for the internal tissues can be advantageously used as a topical solution to keep the external corneal tissues moist many times longer than the balanced salt solution by merely varying the relative concentrations and, therefore, the resulting viscosity of the previously-mentioned intraocular viscoelastic solution that acts as a supplement and substitute for the naturally-occurring vitreous.The different relative concentrations of the two active ingredients in the aforesaid compositions have proven to be far superior to balanced salt solution for topical application to keep the tissues moist during surgery by maintaining a smooth, hydrated cornea under the heat of the operating room microscope light. Moreover, since the two solutions contain the same active ingredients, they are fully compatible and can be used simultaneously to both protect and irrigate the delicate corneal tissues.

Specifically, the topical solution will contain approximately 1% hydroxypropylmethyl cellulose and 20 ppm polyethylene oxide carried in a physiologic saline solution. By way of contrast, the intraocular viscoelastic composition will have the concentration of the hydroxypropylmethyl cellulose increased to 2% while the concentration of the polyethylene oxide is reduced to only 10 ppm. Thus the method being described involves the step of simultaneously irrigating and protecting the delicate corneal tissues using two fully compatible solutions containing the same active ingredients but in different concentrations. When this is done, the stroma and entire cornea is hydrated while the fluid loss through the incision is minimized. It also acts as a tamponade on the scleral flap area.

Since these fluids are aspirated from the eye upon completion of the surgery in order to minimize the incidence of increases in intraocular pressure, a non-toxic and physiologically inert tinting material may be added so that the surgeon can be surer that he or she has removed most of the fluid added during the surgery. The resulting compositions, with or without the dye, have proven to be as effective as hyaluronate-based preparations while being far less expensive and, at the same time, lowering operating room costs due to the more efficient use of personnel that results from the less frequent need for irrigation of the corneal tissues.

From the foregoing, it will be seen that there has been described a protective solution for intracorneal use in eye surgery which has excellent clarity and transparency but, more importantly, much improved elasticity when compared with hydroxypropylmethyl cellulose alone. The mixture has a high-molecular weight which is equally effective if not, in fact, superior to sodium hyaluronate-based products at a fraction of the cost. The solution is safe, non-toxic, readily absorbed, easy to administer, versatile in its application, requires no refrigeration and has a long shelf life.

Claims (6)

1. A viscoelastic aqueous/vitreous substitute for ophthalmic surgery which comprises a solution containing at least approximately 1% hydroxypropylmetbyl cellulose and at least approximately 100 ppm polyethylene oxide in a physiologic balanced salt solution.

2. A substitute according to claim 1, in which the concentration of the hydroxypropylmethyl cellulose is approximately 2%.

3. A substitute according to claim 1 or 2, in which the concentration of the polyethylene oxide is approximately 200 ppm.

4. A method of irrigating and protecting the corneal tissues during ophthalmic surgery which comprises the steps of covering the inner cornea with a physiologic saline solution containing approximately 2% hydroxyprophymethyl cellulose and approximately 10 ppm polyethylene oxide while simultaneously periodically wetting the outer cornea with a compatible physiologic saline solution containing approximately half the hydroxypropylmethyl cellulose and approximately twice the polyethylene oxide.

5. A viscoelastic aqueous/vitreous substitute for ophthalmic surgery, substantially as specifically described.

6. A method of irrigating and protecting the corneal tissues during ophthalmic surgery, substantially as specifically described.