WO1988008709A1

WO1988008709A1 - Improved viscoelastic fluid for ophthalmic surgery and method of using same

Info

Publication number: WO1988008709A1
Application number: PCT/US1988/001389
Authority: WO
Inventors: Phillip E. Pennell; John M. Blackmore
Original assignee: Mdr Group, Inc.
Priority date: 1987-05-04
Filing date: 1988-04-27
Publication date: 1988-11-17
Also published as: EP0359766A1; JPS6464653A; CA1317226C; GB8808983D0; GB2204238A; AU1726088A; EP0359766A4

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

IMPROVED VISCOELASTIC FLUID FOR OPHTHALMIC SURGERY AND METHOD OF USING SAME ^'

BACKGROUND OF THE INVENTION 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 keratoconjunctivitiε sicca and as an emollient. 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.

Additional work confirming these earlier results has been conducted by Dr. Scott M. MacRae who compared the efficacy and toxicity of sodium hyaluronate, methylcellulose and chrondroitin sulfate, 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 favorable 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 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.

FIELD OF THE INVENTION The present invention relates to an improved viscoelastic formulation which when used in dilute form as a topical solution in place of balanced salt solution to keep the corneal surfaces moist lasts up to ten times as long in the eye before having to be renewed. The same unique formulation when used in a different concentration has 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 considerably less expensive. The invention also encompasses the novel method of using the two different yet compatible solutions together during ophthalmic surgery so as to simultaneously protect the cornea and irrigate it without obscuring the surgeon's view of the site in any way.

DESCRIPTION OF THE RELATED ART 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, once again, so far as applicant is aware, heretofore unknown in the art although it is, of course, used as an ingredient in so-called "artifical tears" for treating dry eyes and as a component of contact lens solutions. The closest and most pertinent prior art known to applicant is contained in two U.S. Patents, specifically. Patent No. 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 Irving Katz Patent No. 4,287,175 issued September 1, 1981 for "Contact Lens Wetting Agents", both of the aforementioned patents being assigned to Merck & Co., Inc. The earlier Katz patent teaches the use of hydroxypropylmethy1 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 protecting the delicate epithelial cells in ophalmic 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 intraocular pressure of the type often associated with glaucoma. 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 opthalmic surgery or, for that matter, as a topical moisturizing agent to be used during such surgery as a long-lasting moisturizing agent. SUMMARY OF THE INVENTION

This invention encompasses a novel fluid viscoelastic formulation of variable viscosity for use in ophthalmic surgery containing as its active ingredients a mixture of both hydroxypropylme h l cellulose and polyethylene oxide together with a physiologic buffered saline solution. Hydroxypropylmethyl cellulose is clear, non-toxic and quite viscous, however, it is also essentially non-elastic. It has now been found in accordance with the teaching of the present invention 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. In addition, different relative concentrations of the two active ingredients in the aforesaid composition 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.

It is, therefore, the principal object of the present invention to provide an improved viscoelastic solution for use in ophthalmic surgery which is made up in two different concentrations and administered simultaneously to both protect and irrigate the corneal tissues.

A second object is to provide a solution of the type aforementioned which is susceptible of being made up in selected viscosities by changing the relative concentrations of the active ingredients to adapt it for use as either a topical moisturizing agent or a protective shield for the delicate corneal surfaces and epithelial cells within the inner eye.

Another objective of the invention herein disclosed and claimed is that of providing a topical moisturizing agent which remains effective many times longer than the conventional balanced salt solution while, at the same time, doing a better job.

Still another objective of the within-described invention is to provide 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.

An additional object is to provide a high-molecular weight viscoelastic mixture which is equally effective if not, in fact, superior to sodium hyaluronate-based products at a fraction of the cost.

Further objects are to provide a solution for use in ophthalmic surgery which is safe, non-toxic, readily absorbed, easy to administer, versatile in its application, requires no refrigeration and has a long shelf life. Other objects will be in part apparent and in part pointed out specifically hereinafter in connection with the detailed description of the preferred embodiments which follow.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The anterior chamber of the eye is filled with circulating aqueous, whereas its posterior chamber with vitreous. 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 aqueous 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 completed, 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 hyaluronate-based products is their cost which at the present time runs around $70 or so for less than a cubic centimeter 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 polyethylene oxide, both in a carrier comprising physiologic buffered saline solution.

The other 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, applicant has discovered that a carefully modified 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. 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. In accordance with the teaching found herein, a unique method of simultaneously irrigating and protecting the delicate corneal tissues is taught using two fully compatible solutions containing the same active ingredients but in different concentrations. When this is done, the stroirta 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 intraocular pressure increases, 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 every bit 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.

Claims

CLAIMS What is is claimed is:

1. The 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.

2. The viscoelastic aqueous/vitreous substitute as set forth in claim 1 in which: the concentration of the hydroxypropylmethyl cellulose is approximately 2%.

3. The viscoelastic aqueous/vitreous substitute as set forth in claim 1 in which: the concentration of the polyethylene oxide is approximately 200 ppm.

4. The method of irrigating and protecting the corneal tissues during ophthalmic surgery which comprises: covering the inner cornea with a physiologic saline solution containing approximately 2% hydroxypropylmethyl 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.