A method of performing intra-articular therapy and a dilution resistant viscoelastic composition are disclosed. One embodiment of the dilution resistant composition comprises a hyaluronate-based viscoelastic agent and a low viscosity, polymer-containing solution. The hyaluronate-based viscoelastic can be an aqueous solution sodium hyaluronate having an average molecular weight greater than 750,000 Daltons and a concentration by weight between 0.5% and 3%. The polymer-containing solution can contain a polymer selected from the group consisting of chondroitin sulfate and hydroxypropylmethylcellulose. One embodiment can comprise a polymer-containing solution containing hydroxypropylmethylcellulose at a concentration by weight from about 0.05% to about 5.0% and chondroitin sulfate at a concentration by weight from about 0.1 to about 7%.

Description of the Invention

SUMMARY OF THE INVENTION

The embodiments of the dilution resistant viscoelastic compositions of this invention substantially meet these needs and others. The present invention is directed to improved viscoelastic compositions for performing surgery, especially ophthalmic surgery, and for performing therapies, especially viscoelastic joint therapy, that require an increased resistance to dilution and loss of viscosity and/or varying rheological properties. Embodiments of this invention comprise viscous or viscoelastic agents in combination with an irrigating solution comprising a relatively low molecular weight polymer.

More specifically, the inventive methods of the embodiments of the present invention comprise transitioning the rheological properties (specifically viscosity and cohesiveness) of hyaluronate-based viscoelastic agents while also increasing their resistance to dilution and viscosity loss, by exposing such viscoelastic agents to irrigating solutions containing low levels of relatively low molecular weight biocompatible polymers, such as chondroitin sulfate ("CS"), and cellulosic polymers, especially methylcellulose ("MC") and hydroxypropylmethylcellulose ("HPMC"). The hyaluronate-based viscoelastic, at its interface with the polymer-containing irrigating solution, becomes less cohesive and, at the same time, more viscous. The decreased cohesiveness and increased viscosity of the surface hyaluronate interfacing the irrigating solution in situ renders it less susceptible to unintentional aspiration during a surgical procedure, such as cataract surgery. The hyaluronate material that is further removed from such surface (i.e. deeper within the bolus of material) retains its original lower viscosity and higher cohesiveness, and may therefore be readily aspirated at the conclusion of the surgery. In this manner, the skilled surgeon will be able to enjoy the positive aspects of different rheological profiles using the same hyaluronate-based material by modifying its properties with the polymer-containing irrigating solution to suit the particular phase of a surgery, i.e., capsulorhexis, phacoemulsification or aspiration of the viscoelastic.

A further aspect of the embodiments of this invention is especially applicable to therapies, such as viscoelastic joint therapy, that benefit from the ability of a viscoelastic composition to provide prolonged relief. This ability is directly related to the viscoelastic composition's dilution characteristics. By mixing such viscoelastic agents as described herein, the properties of the combined product are such that the resulting composition has an increased resistance to dilution whether by an exogenous or endogenous addition. Viscosity of the therapeutic agent can thus be maintained and its effectiveness prolonged.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

While particularly important in ophthalmic surgery, and especially cataract surgery, the methods and compositions of the present invention may be utilized in any viscosurgical procedure with a hyaluronate-based viscoelastic, and especially those in which there is concern over unintentional or premature removal of the viscoelastic material from the surgical site. In cataract surgery, the anterior chamber of the eye, i.e., the space between the iris and the corneal endothelium is filled with viscoelastic. The viscoelastic serves two purposes: (1) maintaining the corneal dome to give the surgeon an unobstructed view of the interior surgical site, and (2) protecting the delicate endothelial cells of the cornea by coating them. As discussed above, unsuccessful attempts have been made to find a viscoelastic material with a single, optimized rheology that achieves both of the foregoing objectives. Another approach has been to utilize separate cohesive and dispersive viscoelastic agents in the same surgical procedure. The DuoVisc.RTM. product marketed by Alcon Laboratories, Inc. utilizes this latter approach, and has enjoyed commercial success. Nevertheless, it would be preferable if the dual functions of the viscoelastic could be served by a single viscoelastic material. That objective is met using the methods and compositions of the present invention. The various embodiments of the viscoelastic compositions of this invention are also well suited for use as vitreous replacements in, for example, a vitreo-retinal surgery, and such use is contemplated to be within the scope of this invention.

Because of their ability to achieve enhanced retention times when injected into the body, the viscoelastic compositions of the present invention are also well-suited for joint therapy through intra-articular injection. The effect of conventional hyaluronate is temporary because the material remains within the articular chamber for only about 72 hours before it is absorbed and/or metabolized. The benefit of the longer retention times afforded by the compositions of the present invention is readily apparent, as the therapeutic effects of intra-articular viscotherapy with the compositions of the present invention should outlast those obtained with conventional viscoelastics. In a preferred embodiment, the compositions of the present invention for use in joint therapy will contain chondroitin sulfate, which is known to be particularly beneficial for human and animal joints. U.S. Pat. No. 5,498,606, the entire contents of which are by this reference incorporated herein, discloses the antiinflammatory and cell protective effects observed upon intra-articular injection of chondroitin sulfate in horse joints. More recently, it has been suggested that the intra-articular injection of VISCOAT, which contains a mixture of sodium hyaluronate and chondroitin sulfate, may cause cartilage regeneration in the joints of patients suffering from grade I and grade II osteoarthritis. In that regard, the contents of commonly assigned U.S. patent application Ser. No. 10/082,743 are by this reference incorporated herein.

By using an irrigating solution that contains relatively low concentrations of lower molecular weight polymers such as HPMC, MC and CS, the rheology of a cohesive, hyaluronate-based viscoelastic material at the interface of the viscoelastic and the irrigating solution is significantly altered. The viscoelastic at such interface becomes less cohesive and more viscous, thereby minimizing inadvertent or premature aspiration and removal of the protective viscoelastic material from the eye. The term "hyaluronate-based viscoelastic" as used herein means any aqueous solution of hyaluronic acid or physiologically acceptable salts thereof, which is free of any significant amount of any low molecular weight, non-HA polymer. With the exception of Viscoat.RTM., all of the commercial HA products described above are considered hyaluronate-based viscoelastics. As used herein, a "cohesive" hyaluronate-based viscoelastic would include any hyaluronate-based viscoelastic containing a hyaluronate component with a molecular weight of approximately 1,000,000 Daltons or more.

Lens removal surgery, such as cataract surgery, or the less common clear lensectomy, involves several different steps or phases. As previously discussed, differing rheological profiles may be preferred for the viscoelastic used in each of those steps or phases. For example, during capsulorhexis (opening of the capsular bag to expose the clear or cataractous lens), it is desirable to have a cohesive viscoelastic for space maintenance; during phacoemulsification (ultrasonic fragmentation of the lens) it is desirable to have a dispersive viscoelastic for better coating and maneuverability; finally, during artificial lens insertion and completion of the surgery, it is desirable to have a cohesive viscoelastic both for space maintenance and ease of removal. By using a polymer-containing irrigating solution, as described more fully below, with any of the conventional hyaluronate-based viscoelastic agents, one can, using the methods of the present invention, secure the preferred rheological profile at each step of the procedure.

One embodiment of the present invention comprises the following steps. A cohesive viscoelastic like PROVISC.RTM. (Alcon Laboratories, Inc., Fort Worth, Tex.), HEALON.RTM., or HEALON GV.RTM.. (Pharmacia & Upjohn, Peapack, N.J.), or AMVISC.RTM. PLUS (Bausch & Lomb Surgical, Claremont, Calif.) is used before and during the capsulorhexis step. Immediately prior to commencing phacoemulsification, a small amount of polymer-containing irrigating solution is permitted to flow, without aspiration into the space separating the viscoelastic from the anterior surface of the exposed, typically cataractous lens. The phaco emulsification device is then engaged, without irrigation/aspiration, and the tip of the phaco emulsification handpiece is introduced into the surgical site and placed in the irrigating solution above the exposed lens. The ultrasonic waves from the tip of the phaco emulsification handpiece will promote the mixture of the irrigating solution and the viscoelastic agent at the interface of those two substances. This will change the cohesive property of the hyaluronate-based viscoelastic in the immediate vicinity of the lens rendering the viscoelastic more dispersive. After one to twenty seconds of mixing, the phacoemulsification of the lens, with irrigation/aspiration, is completed in the ordinary manner. At the end of surgery, the irrigation aspiration tip may be inserted into the bolus of viscoelastic material in the anterior chamber, i.e., beyond the more dispersive surface material at the interface and into the material not effected, or less effected, by admixture with the polymer-containing irrigating solution. The viscoelastic material in this region remains more cohesive and is therefore easily aspirated out with minimal effort and minimal trauma to the delicate endothelial cells.

The cohesive, hyaluronate viscoelastics suitable for use in the methods of the present invention include those commercial products identified above, which may generally be characterized as containing sodium hyaluronate (of course other physiologically acceptable hyaluronate salts could also be used) having average molecular weights greater than 500,000 Daltons, preferably from about 1,000,000 to about 5,000,000 Daltons, and concentrations from about 1.0 to about 3.0% by weight.

Irrigating solutions that may be used in the methods of the present invention include any sterile, aqueous irrigating solution suitable for surgery. Preferred are balanced salt solutions such as BSS.RTM. or BSS PLUS.RTM. (Alcon Laboratories, Inc., Fort Worth, Tex.). The addition of polymers to the irrigating solution may be effected in the manner described in U.S. Pat. No. 5,409,904, previously incorporated by reference. Preferred polymeric components for the irrigating solution include CS, MS and HPMC. The relatively low weight CS suitable for purposes of the present invention would include material having an average molecular weight of less than about 100,000 Daltons, preferably from about 20,000 to about 80,000 Daltons, and most preferably from about 30,000 to about 50,000. HPMC or MC used as the polymeric component of the irrigating solution in the present methods will have an average molecular weight below about 400,000 Daltons and, preferably from about 50,000 to about 200,000 Daltons, and most preferably from about 70,000 to about 100,000 Daltons. Concentration ranges for the polymeric components will vary depending upon the molecular weight of the polymeric component chosen, but should be maintained at levels low enough to retain the flow properties desired for an irrigating solution. For CS, the concentration in the irrigating solution may be from 0.1 to 10% by weight, preferably from 0.5 to about 7%, and most preferably from about 2% to about 5% by weight. For HPMC and MC, the concentration in the irrigating solution may be from 0.05 to 5%, preferably from about 0.1 to about 0.5%, and most preferably from about 0.2 to about 0.3%. Combinations of different low molecular weight polymers, as exemplified below, may also be used. For intra-articular use, the viscoelastic compositions of the present invention are mixed without an irrigation solution. The low molecular weight polymers are mixed with a hyaluronate-based viscoelastic, as discussed below, to achieve the properties described herein.
 

Claim 1 of 3 Claims

1. A method of performing intra-articular therapy comprising: introducing a dilution resistant viscoelastic composition into the site of the intra-articular therapy, wherein the dilution resistant viscoelastic composition comprises: a hyaluronate-based viscoelastic agent, wherein the hyaluronate-based viscoelastic is an aqueous solution sodium hyaluronate having an average molecular weight greater than 750,000 Daltons and a concentration by weight between 0.5% and 3%; and a low viscosity polymer, wherein the polymer is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, and combinations thereof, and wherein said polymer is present at a concentration of at least about 0.2% by weight.
 

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