NO20032010L - Non-aspirational transition viscosities for use in surgery - Google Patents

Description

FIELD OF THE INVENTION

The present invention relates to the field of viscous and viscoelastic materials which are suitable for use in surgical procedures. More specifically, non-aspirating viscoelastic materials are described, including transient viscoelastic materials (having non-shear-related variable viscosity) that can be left in situ after surgery is completed. Procedures using transient viscoelastic materials in surgery, particularly ophthalmic surgery, are also described.

BACKGROUND OF THE INVENTION

Viscous or viscoelastic materials used in surgery can serve a number of different functions, including, but not limited to, soft tissue preservation and support, tissue manipulation, lubrication, tissue protection, and adhesion inhibition. It is understood that the different rheological properties of these materials will necessarily affect their ability to perform these functions, and thus their suitability for certain surgical procedures. See e.g. US Patent No. 5,273,056.

Cataracts are opacities in the ocular lens that generally occur in the elderly. To improve vision, the cataract-containing lens is surgically removed, and an artificial intraocular lens is inserted instead. During this surgical procedure, viscoelastic materials are usually injected into the anterior chamber and capsular bag to prevent the anterior chamber from collapsing and to protect tissue from damage caused by physical manipulation.

A number of viscous or viscoelastic materials (hereafter "materials") are known for use in ophthalmic surgery. E.g. is "Viscoat<®>" (Alcon Laboratories, Inc.), which contains sodium hyaluronate and chondroitin sulfate; "Healon<®>" and "Healon<®>GV" (Pharmacia Corp.), "Amvisc<®>Regular" and "Amvisc<®>Plus" (IOLAB) and "Vitrax<®>" (Allergan), which all contain sodium hyaluronate; and "Cellugel<®>" (Alcon), containing hydroxypropylmethylcellulose (HPMC), useful in cataract surgery. They are used by the skilled ophthalmic surgeon for several purposes, including preservation of the anterior chamber of the eye and protection of ophthalmic tissues during surgery, especially corneal endothelial cells, and as an aid in the manipulation of ophthalmic tissues.

Although all the materials described above can be used

during cataract surgery, they all have their known advantages and disadvantages. See US Patent No. 5,273,056. In general, however, all such materials that have a sufficiently high viscosity and pseudoplasticity to be useful in ophthalmic surgery will cause a transient elevation of the intraocular pressure (IOP), known as an IOP spike. "), if they are left in the eye after surgery. (See Obstbaum, Postoperative pressure elevation. A rational approach to its prevention and management, J. Cataract Refractive Surgery 18:1

(1992).) The elevated pressure has been attributed to the agent's disruption of the normal outflow of aqueous fluids through the trabecular meshwork and Schlemm's canal. (See Berson et al., Obstruction of Aqueous Outflow by Sodium Hyaluronate in Enucleated Human Eyes, Am. J. Ophthalmology, 95:668

(1983); Olivius et al., Intraocular pressure after cataract surgery with Healon<®>, Am. Intraocular Implant Soc. J. 11: 480 (1985); Fry, Postoperative intraocular pressure rises: A comparison of Healon, Amvis, and Viscoat, J. Cataract Refractive Surgery 15: 415 (1989).) Depending on their magnitude and duration, IOP peaks can cause significant and/or irreversible damage to sensitive ocular tissues, including but not limited to the optic nerve.

How easily a material can be removed from the surgical site, usually by suction, has therefore traditionally been considered to be an important property in the overall assessment of the agent's usefulness in cataract surgery. By removing the agent before surgery ends, the surgeon hopes to minimize or avoid a noticeable IOP peak. However, removal of materials that are relatively dispersive (as opposed to cohesive) or adhere to the ocular lens is often difficult and can cause additional trauma to the eye.

An exogenous dilution of the viscoelastic material has been proposed to attenuate IOP peaks. See US Patent No. 4,328,803. However, depending on the particular viscoelastic material and the surgical technique used, IOP peaks may still be a problem. More recently, it has been suggested that the administration of degrading materials to break down conventional viscous or viscoelastic materials in the eye may attenuate or avoid the occurrence of IOP peaks. See e.g. US Patent No. 5,792,103. Such a method not only requires the administration of a second, enzymatic material into the eye, the biocompatibility of which must be ensured; but also a way to mix the two materials sufficiently well together in a special device.

Viscoelastic materials have also been promoted as drug delivery devices for pharmaceutical materials that are administered when the viscoelastic materials are delivered during surgery. E.g. US Patent No. 5,811,453 (Yanni et al.) describes viscoelastic materials containing anti-inflammatory compounds, and methods of using these improved viscoelastic materials in cataract surgery. Although this method can attenuate ocular inflammation caused by surgical trauma, it still has a significant limitation in that it entails problems with IOP peaks, as described above. Thus, these improved viscoelastic materials must still be suctioned out after surgery is completed.

There is therefore a need for an improved way to attenuate or avoid IOP peaks associated with the use of conventional viscous or viscoelastic materials in ophthalmic surgery, especially cataract surgery. More specifically, we saw a need for an improved viscous or viscoelastic material which has a variable or transient viscosity such that without the addition of degrading agents it will become significantly less viscous after it has served its purpose in surgery, as such materials hereinafter shall be termed transient viscoelastic materials. The surgeon can thus leave a significant amount of such transient viscoelastic materials in the eye, which will be eliminated by the body's natural processes without causing any dangerous IOP peak.

Transient viscosity is known to occur in certain systems. Within the ophthalmic field, there are known systems where a liquid forms a gel after application to the eye. E.g. can such gelatinization be triggered by a changed pH value. See Gurney et al., "The Development and Use of In Situ Formed Gels, Triggered by pH", Biopharm. Ocul. Drug Delivery

(1993), pp. 81-90. Temperature-tolerant gelation systems have also been observed for certain ethyl (hydroxyethyl) cellulose ethers (EHECs) when these are mixed with certain ionic surfactants in suitable concentrations (see Carlsson et al.,

"Thermal Gelation of Nonionic Cellulose Ethers and Ionic Surfactants in Water", Colloids Surf., vol. 47, pp. 147-165

(1990)) and for systems of pure methyl ethyl cellulose (US Patent No. 5,618,800 (Kabra et al.)). More recently, US Patent No. 6,177,544 describes a modified collagen for ophthalmic use, which was described to lose viscosity after denaturation, to facilitate its removal. However, no commercial versions of such a material are known. It is also known that mug carrageenans can be tailored to adjust their viscosity transitions within different temperature ranges. (See Verschueren et al., "Evaluation of various carrageenans as ophthalmic viscolysers", STP Pharma Sei, vol. 6, pp. 203-210 (1996) and Picullel et al., "Gelling Carrageenans", Food Polysaccharides and Their Applications, eds Stephen, A.M., Marcel Dekker: New York, vol. 67, pp. 204-244 (1995).) Finally, gellan gum (gellan gum, "Gelrite<®>") is known to form a gel upon contact with specific materials. Greaves et al., "Scintigraphic Assessment of an Ophthalmic Gelling Vehicle in Man and Rabbit", Curr. Eye Res., vol. 9, p. 415 (1990). Gellan systems have been proposed for use as vehicles for ophthalmic drugs (Rozier et al., "Gelrite: A Novel, Ion-Activated, In Situ Gelling Polymer for Ophthalmic Vehicles. Effect on Bioavailability of Timolol", Int. J. Pharm. , vol. 57, p. 163 (1989)), and one gellan system is currently marketed with timolol, a beta blocker, as a glaucoma drug.

However, the use of non-collagen-based viscoelastic materials with transient viscosity as effective surgical tools, especially in ophthalmic surgery, has neither been described nor suggested in the prior art. To be most effective for use as an ophthalmic surgical tool, the agent, in addition to having the desired initial viscosity and transient viscosity within the specified temperature range, should preferably meet the following requirements: physiologically acceptable osmolality and pH; relatively short viscosity transition time; clear (without turbidity); bio-compatible; and sterilizable. It is believed that the transient viscoelastic materials according to the present invention meet these requirements.

SUMMARY OF THE INVENTION

The present invention relates to improved viscous or viscoelastic materials for use in surgical procedures, especially ophthalmic surgical procedures. More specifically, the present invention targets any such material with the desired initial viscosity which provides an acceptable IOP peak profile in the IOP peak model to be described in the following. The improved materials of the present invention include transiently viscous or viscoelastic polymeric materials suitable for use in ophthalmic surgery. As used herein, the term "transient viscoelastic material" means a material that retains a high viscosity during the surgical procedure, but rapidly loses viscosity after completion of surgery, to attenuate or avoid the occurrence of dangerous IOP peaks, and to reduce or avoid the need for an active removal of the viscoelastic material after the end of the surgical procedure.

As the surface temperature of the eye tissues during surgery will approach room temperature, i.e. 25°C or less, we have discovered materials that will retain a suitable viscosity at this temperature, but will quickly lose viscosity at a slightly higher temperature (i.e. body temperature, about 37°C). The loss of viscosity, which takes place without any exogenous addition of degrading materials, is primarily caused by the eye rewarming to body temperature after the end of surgery.

The stability of the transient viscoelastic materials according to the present invention is a particularly important feature of the present invention. If the agent undergoes any significant hydrolysis, oxidation or other degradation prior to use, the agent may lose its viscous properties and yield a useless or less useful viscoelastic material. The preferred transient viscoelastic compositions of the present invention are substantially stable in that they exhibit less than 1% degradation for up to 6 months at storage temperature. These compositions will produce little or no IOP peak (as defined below) when used and may remain in the eye after routine cataract surgery.

Substances suitable for use as transient viscoelastic materials include, but are not limited to, hydrophobically modified polysaccharides or mucopolysaccharides such as hyaluronic acid and its salts (HA) (with or without surfactants); dialyzed polyampholytes or dialyzed mixtures of oppositely charged polyelectrolytes; polysaccharides or mucopolysaccharides such as HA with cationic hydrophilic polymers; polysaccharides and hydrophilic synthetic polymers with temperature-dependent conformational transitions; and combinations thereof. Preferred are hydrophobically modified polysaccharides or mucopolysaccharides. Most preferred are hydrophobically modified HA<1>s, especially HA amides.

DETAILED DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graph depicting viscosity as a function of concentration for dodecylamide-HA of the present invention and control HA. Fig. 2 is a graph depicting viscosity as a function of shear rate for octylamide-HA according to the present invention. Fig. 3 is a graph depicting the transient viscosity of octylamide-HA according to the present invention. Fig. 4 is a graph depicting the viscosity stability of autoclaved dodecylamide-HA according to the present invention. Fig. 5 is a graph depicting the stability of the transition behavior of hexadecylamide-HA according to the present invention. Fig. 6 is a graph depicting the rate of hydrolysis of esterified HAs according to the present invention. Fig. 7 is a diagrammatic representation of the IOP peak model according to the present invention. Fig. 8 is an exploded view of a perfusion device according to the present invention. Fig. 9a is a top view of an eye for use in a perfusion device.

Fig. 9b is a side view of the eye in fig. 9a.

Fig. 10 is a cross-section through the perfusion device according to the invention in fig. 8, where a front segment is incorporated. Fig. 11 is a graph depicting the effects of traditional viscoelastic materials and of a transient viscoelastic material of the present invention on the IOP value using the IOP peak model of the present invention.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to viscoelastic materials, and in particular transient viscoelastic materials, compositions and methods of application. The primary area of use for the transient viscoelastic materials is in surgical applications where the transient viscoelastic material is used during surgery in its more viscous state, and after surgery loses considerable viscosity in situ. A preferred application of the transient viscoelastic materials is in cataract surgery, where the viscoelastic material is instilled (i) into the anterior chamber of the eye to preserve the vault and protect the exposed tissues; and/or (ii) in the back chamber to inflate the capsule bag. After surgery, the remaining viscoelastic material in the eye is warmed by the body to ambient body temperature, loses its viscosity and can be removed more easily (than non-transient viscoelastic materials) by the processes of the eye. The main advantage of this preferred use is that you avoid the IOP peak that can occur with other systems. Another advantage of this application is that it gives the surgeon the traditional advantages of a viscoelastic material, without the disadvantage of having to thoroughly suck up the viscoelastic material from the surgical site after the surgery is finished. As was mentioned above, such suctioning is time-consuming and poses a further danger to the patient.

The transient viscoelastic materials of the present invention typically exhibit a viscosity loss of 70% or more, without any significant hydrolysis, when such materials undergo a temperature change from about room temperature or surgical temperature (approx. 17-26°C) to approx. body temperature (approx. 35-38°C) .

As was mentioned above, the preferred transient viscoelastic materials according to the present invention will essentially be stable. As used herein, "substantially stable" refers to viscoelastic materials that lose only 1% or less of their hydrophobic side chains by hydrolysis, oxidation, or other degradation, when such viscoelastic materials are stored at refrigerator temperature around 4°C for up to 6 months.

The transition property of the viscoelastic materials according to the present invention is preferably reversible. The reversible viscosity property of the preferred embodiments enables the transient viscoelastic materials to be heated prior to use, e.g. heat sterilization, and then cool them for a surgical application.

Further preferred properties of the transient viscoelastic materials according to the present invention include (1) a transition time of less than approx. 2 hours after the procedure; (2) optically clear gels with little or no turbidity; (3) a secure adhesion to ocular tissue (ie, an ability to provide a protective coating on sensitive tissues); and (4) biocompatibility.

As mentioned above, the most important feature of the transient viscoelastic materials of the present invention when used in cataract surgery procedures is that they will cause little or no IOP peak after such surgery. For the purposes of the present invention, a transient viscoelastic material is considered to exhibit "little or no IOP peak" if 0.5 ml of a 10% solution (ie, the actual product composition diluted to 10% of its original concentration with a buffered isotonic saline solution) produces an IOP peak that is no more than the average approx. 10 mm Hg above the baseline IOP value in a validated IOP peak model (the "IOP peak model") to be described below.

Although we do not wish to commit ourselves to any particular theory,

we believe that the transient viscoelastic property of the compositions according to the present invention can be attributed to physical connections between molecules with a relatively low molecular weight, which leads to a viscosity that is higher than what would be expected from such molecules with a low molecular weight in a given concentration. Generally, the transient viscoelastic materials according to the present invention are modified viscoelastic materials where hydrophobic side chains have been covalently bonded to the viscoelastic compounds. The unmodified viscoelastic materials can be substituted to varying degrees with various units to provide transient viscoelastic materials according to the present invention. For example, all the relevant side chains (e.g. the carboxylate side chains for transient viscoelastic ester and amide materials) of the viscoelastic materials can be substituted (ie 100% substitution), or only part of the side chains, e.g. 15% substitution. Generally

transient viscoelastic materials will be derived from known viscoelastic materials and modified to exhibit the properties described above. Examples of commercially available viscoelastic materials useful in the preparation of transient viscoelastic materials include salts of hyaluronic acid (eg, sodium hyaluronate (HA)), chondroitin sulfate (CS), and hydroxypropylmethylcellulose (HPMC) and a combination of HA and CS. Other viscoelastic materials useful in the manufacture of past-

walking viscoelastic materials include dialyzed polyampholytes, such as carboxymethyl cellulose.

The transient viscoelastic materials may be composed of viscoelastic polymers of varying molecular weight. In general, the average molecular weight of the unmodified polymer will vary from 50,000 to 1,000,000 Da. For HA-based transient viscoelastic materials, the average molecular weight of the unmodified HA polymer base structure will preferably vary from approx. 120,000 to approx.

400,000 Da (weight averages. molecular weight) and from approx. 50,000 to approx. 350,000 Da (number average molecular weight). These preferred unmodified HAs will, in conventional concentrations, exhibit an insufficient viscosity for the preferred surgical applications. The molecular weight of viscoelastic materials can be calculated by gel permeation chromatographic (GPC) methods, also known as size exclusion chromatography (SEC), with detection by light scattering or against standards of known molecular weight, using refractive

index detection. The molecular weight usually affects the degree of viscosity of these known viscoelastic materials. All molecular weights given for the transient viscoelastic materials described herein are, unless otherwise stated, the number average molecular weight of the unmodified viscoelastic polymer prior to modification to provide a transient viscoelastic material.

The HAs (free acid and salt form) can be modified to exhibit the above-mentioned properties, and thus be useful as transient viscoelastic materials according to the present invention. E.g. dodecyl units can be covalently attached to the carboxylic acid groups in the basic structure of the HAs to form dodecyl esters thereof. As used herein, HAs that have been modified by esterification of their side chains with different units are termed "HA esters". Examples of esters that can be substituted on the carboxylate groups of HA include, but are not limited to, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl , decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or any other alkyl groups containing up to 30 carbon atoms; cycloalkyl groups, e.g. cyclohexyl; and aryl groups, e.g. phenyl; and any isomers of the above groups. Such substituents may optionally be further substituted, and may optionally contain heteroatoms selected from the group consisting of 0, N and S. Such HA esters are available from Fidia Advanced Biopolymers (Abano Terme, Italy), or may also be synthesized by methods which are known in the field, e.g. US Patent Nos. 5,466,461; 5,616,568; and 5,652,347; the contents of which are incorporated herein by reference. The degree and type of such substitution will affect the low shear or apparent viscosity and low shear cohesion, as well as the viscosity and cohesion at elevated temperature. Preferred are hydrophobic substituents.

As there are several factors that influence the rheological properties of compositions according to the present invention (e.g. the type and degree of substitution and the average molecular weight and concentration of the viscoelastic polymer (unmodified), different compositions with different parameters can give similar rheological properties. For example, a 0.88% w/v solution of a 200 kDa HA that is 14% substituted with dodecylated carboxyl groups, a 1.2% w/v solution of a 200 kDa HA that is 11% substituted with dodecylated carboxyl groups, and a 2.55% w/v solution of a 200 kDa-HA that is 4% substituted with hexadecylated carboxyl groups, similar viscosity and transition behavior. The transient viscoelastic materials of the present invention can thus be characterized by a "viscosity factor " which is determined with the following formula: Concentration , . Æ.. Viscosity-, , . , -i o i (unmodified x u 4. 4. * i 4. ; wt/vol-% poly ymer in kDa) \ sub stitusIon factor; Transient viscoelastic materials according to the present; invention will have a viscosity factor from approx. 200 to approx. 50,000. Preferred transient viscoelastic materials according to the present invention will have a viscosity factor from approx. 1,000 to approx. 20,000. Most preferred are transient viscoelastic materials that have a viscosity factor from approx. 2,000 to approx. 10,000. In the same way that a person skilled in the art will understand that compositions with different parameters can give similar rheological properties (see the section above), it will also be understood that due to the interaction between the parameters, compositions with the same or similar viscosity factor can have significantly different rheological properties. The viscosity factor is only a general indicator of the suitability of a viscoelastic composition for the purposes in question. The person skilled in the art will also understand that optimal rheological properties can be achieved for a given purpose by modifying one or more parameters. Preferred modified hyaluronates comprise the partial amide modification of the carboxylate groups of HA with alkyl or aryl groups to form alkyl or aryl amides of HA. As used herein, such molecules are termed "HA amides". Examples of amides that can be substituted on the carboxylate groups of HA include, but are not limited to, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, ;octyl, nonyl , decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or any other alkyl groups containing up to 30 carbon atoms; cycloalkyl groups, e.g. cyclohexyl; and aryl groups, e.g. phenyl; and any isomers of the above groups. Such substituents may optionally be further substituted, and may optionally contain heteroatoms selected from the group comprising 0, N and S. The most preferred amide-substituting group is dodecyl. ;The degree of substitution can also vary. In general, the substitution will be from approx. 2 to 60%. The preferred degree of substitution will be from approx. 5 to 40%. Preferred amide-substituting groups are octyl, dodecyl and hexadecyl; where dodecyl is most preferred. For octylamide HAs, the preferred variables are: degree of substitution from 30 to 40%; polymer concentration from 1 to 3% by weight; and molecular weight of the unmodified HA from 200 to 350 kDa (weight averages) or 120 to 230 kDa (number averages). For the dodecylamide HAs, the preferred variables will be: degree of substitution from 5 to 32%, more preferably 15 to 25% and most preferably 10-20%; polymer concentration from 0.35 to 1.2% by weight; and molecular weight of the unmodified HA from 200 to 350 kDa (weight averages) or 120 to 230 kDa (number averages). Alternatively, an unmodified HA of lower molecular weight can be used. Preferred parameters for such a lower molecular weight transient viscoelastic material would be: unmodified HA with a molecular weight from 50 to 150 kDa (weight averages), amide (preferably dodecyl) degree of substitution from 25 to 40%; and a polymer concentration from 0.5 to 2% (w/v). For the hexadecylamide HAs, the preferred variables will be: degree of substitution from 5 to 15%, polymer concentration from 0.3 to 0.8% by weight; and molecular weight of the unmodified HA from 200 to 350 kDa (weight averages) or 120 to 230 kDa (number averages). The degree of substitution can be determined by NMR as described in example 11. In most cases, the degree of substitution stated in the attached examples was provided by the supplier of HA amides, namely Fidia Advanced Biopolymers. The transient viscoelastic compositions of the present invention will generally have a sufficient zero-shear viscosity to be useful in viscosurgical procedures. Typically, the zero-shear viscosity will be at least 1 Pa-s at 25°C. Compositions exhibiting a zero-shear viscosity from approx. 5 to 10,000 Pa-s at 25°C are preferred. Most preferred are those that exhibit a zero-shear viscosity from approx. 40 to 1,000 Pa-s at 25°C. The HA amides can be obtained commercially from Fidia Advanced Biopolymers (Abano Terme, Italy), they can be synthesized by methods described by Danishefsky and Siskovic in "Conversion of Carboxyl Groups of Mucopolysaccharides in Amides of Amino Acid Esters", Carbohydrate Res. Vol. 16, pp. 199-205 (1971), Bulpitt and Aeschlimann, "New strategy for chemical modification of hyaluronic acid: Preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels", Biomed. Mater. Res., vol. 47, pp. 152-169 (1999), or they can be synthesized by other methods. WO 00/01773 (Bellini et al.), which describes amides of HA and a process for their preparation, is incorporated herein by this reference. This publication generally describes the use of such amides as vehicles for the delivery of drugs for use in viscoelastic surgery or in ophthalmic surgery, but neither describes nor suggests the new compositions and methods according to the present invention. Other transient viscoelastic materials according to the present invention include modified HAs where the hydrophobic group is attached to the HA structure via the hydroxyl units, the N-acetamide units or the carboxyl groups and has been converted to form hydrophobic amine side chains ("HA amines" ), ether side chains ("HA ethers"), thioether side chains ("HA thioethers") or alkyl side chains ("HA alkyls"). Examples of such transient viscoelastic materials include HA-alkylethers, HA-alkylamines, HA-alkylthioethers, HA-alkylcarbamates, HA-alkylthiocarbamates, HA-alkylthioureas and HA-alkylureas, where the alkyl group can be methyl, ethyl, propyl, isopropyl, butyl, sec -butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or any other alkyl group containing up to 30 carbon atoms ; and any isomer of the alkyl group, including cycloalkyl and aryl isomers. Such transient viscoelastic materials can e.g. prepared by the methods described in March, Advanced Organic Chemistry - Reactions, Mechanisms, and Structure, John Wiley&Sons: New York, 4th ed., 1992. ;Chondroitin sulfate (CS) of different molecular weights can be modified in a similar way to HA<1> one, as described above, to provide transient viscoelastic materials according to the present invention. E.g. the carboxylate groups can be amidated analogously to what was described for HA. In addition, the hydroxyl or N-acetamide units of the chondroitin sulfates can be converted to hydrophobic amines, ethers, thioethers, carbamates, thiocarbamates, ureas and thio-ureas in the same manner as described above for HA, using the same alkyl- , cycloalkyl and aryl substituents, to provide transient viscoelastic materials according to the present invention. Examples of such transient viscoelastic materials include CS-alkylethers, CS-alkylamines, CS-alkylthioethers, CS-alkylcarbamates, CS-alkylthiocarbamates, CS-alkylthioureas and CS-alkylureas, where the alkyl group can be methyl, ethyl, propyl, isopropyl, butyl, sec -butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or any other alkyl group containing up to 30 carbon atoms; and any structural isomer of such group, including cycloalkyl and aryl isomers. Such transient viscoelastic materials can be prepared by methods described in March, Advanced Organic Chemistry - Reactions, Mechanisms, and Structure, John Wiley & Sons: New York, 4th ed., 1992. ;The following examples 1-6 are examples of preferred compositions according to the present invention: ; The following examples 7-18 illustrate the rheological properties of the compositions according to the present invention. ;Example 7;The rheological properties of the HA-amide compositions according to the present invention were compared with an analogous non-transient HA composition in different concentrations. The 10% substituted dodecylamide-HA formulations from Example 3 (0.2%, 0.4%, 0.6%, 0.8% and 1.0% w/v) and control compositions containing the non- modified precursor HA in the concentration of 0.2, 0.4, 0.6, 0.8 and 1.0% were prepared according to the following procedure. Containers containing the various formulations were capped and heated for 4 days at 50°C, swirling occasionally to ensure that all dodecylamide HA or HA powder was immersed in the buffered liquid and that the a complete dissolution took place. Each solution was then transferred to a separate 5 ml syringe, stoppered and centrifuged at 2500 rpm to remove bubbles. The filled syringes were then each configured with an empty 5cc syringe via a "Dual-hub" assembly. The syringes were cooled for one hour and mixed using 50 passes on each assembly. To perform rheological analyses, samples were aspirated into a CS-10 ("Constant Stress Rheometer") sample plate from Bohlin through 27 "gauge" needles, with the instrument set in viscometry mode. The viscosity of the samples was measured against the shear rate, using a shear load of 1.09 to 52.89 Pa at 16°C. A shear sweep was used that was as close to the maximum as feasible, taking into account a possible loss of sample due to the centripetal forces at the high shear end. For each sample, the transition behavior (viscosity versus temperature) was then characterized, using a temperature range from 10°C to 50°C and a heating rate of 2.5°C/min. Each sample was processed using identical parameters. The results are summarized in table 1. ; ; As can be seen from Table 1, the dodecylamide-HA compositions were much more viscous than the unmodified HA compositions. Moreover, an increase in the low-shear viscosity correlated with approx. 5 orders of magnitude, with an elevated dodecylamide-HA concentration (ie from 0.2% to 1.0% w/v). ;Example 8;The composition from Example 4 was evaluated rheologically. The composition was prepared in a manner similar to that described in Example 6. This sample was rheologically processed using a Bohlin CS-10 controlled stress rheometer for viscosity versus shear rate using the same procedures as described in example 6, with shear stress in the order of 0.41 to 32.58 Pa. The results are shown in Table 2. ;As can be seen from Table 2, the 1% solution exhibited a low shear viscosity of approximately 1,000 Pa-s. ;In an analogous experiment the viscosity of the composition was tested over a temperature range from 17°C to 27°C, with a shear load of 1.781 Pa. The results are given in Table 3. As can be seen from Table 3 and illustrated in Fig. 3, the transition viscosity loss behavior of this material correlates linearly with an elevated temperature. The overall viscosity loss over the temperature range was about 88%. ;Example 9;The storage stability of preferred compositions of the present invention, as a measure of retained viscosity, was obsd. rvert in the following experiment. The dodecylamide HA from Example 2 was incubated at 4°C and room temperature ("RT", ie 21-23°C) for 5.5 months. At a given time, an aliquot of each composition was taken and a rheological analysis (the shear stress range for this example was from 0.16 to 52.89 Pa) was performed on the sample. The results are listed in table 4 and illustrated in fig. 4th; As can be seen from Table 4, the dodecylamide-HA compositions showed an initial viscosity shift of 16 Pa-s at low shear conditions between time zero the control and after 1 month incubation time. However, the viscosity was stable from 1 month of incubation to 5.5 months of incubation. ;The transient stability of the hexadecylamide-HA compositions stored at 4°C for 5.5 months was also tested. The results are shown in table 5. ; As can be seen from table 5 and fig. 5, the viscosity of all compositions shifted over the temperature change from 25°C to 37°C, losing between 70% and 80% of their viscosity at a shear load of 2.89 Pa. This is in contrast to a viscosity loss of only approx. 35% for hyaluronic acid solutions with similar initial viscosity. Example 10 The stability of a dodecylamide-RA composition according to the present invention was observed with the following experiment. The 1% w/v dodecylamide-HA composition from Example 7 was incubated at 4°C, room temperature (21-23°C) and 37°C for 6 months. At appropriate times, an aliquot of the composition was taken, and the chemical stability of the dodecylamide-HA was analyzed using capillary gas chromatography (GC). GC was performed on a Hewlett Packard 5890A-GC system equipped with a flame ionization detector (FID), using the following parameters: ; The column used was a DB5 fused silica capillary column (30 m long with an inner diameter of 0.32 mm and a film thickness of 1.0 mm) from J&W Scientific (Folsom, CA). ;After a given incubation period, samples were mixed with one weight equivalent of a mixture of two parts ethyl acetate and one part ethanol (also calculated by weight) and incubated at 50°C for one hour. To this mixture was added three more parts by weight of the ethyl acetate/ethanol mixture. This second addition caused a precipitate of the polysaccharide, which was centrifuged together, and the supernatant was analyzed by GC for the presence of the hydrophobic leaving group dodecylamine. If 100% hydrolysis of the dodecylamine-HA side chains occurred, complete precipitation of the 10% substituted dodecylamine-HA would result in 42 ppm dodecylamine in the supernatant. The test results showed that there was less than 1 ppm of dodecylamine in the supernatants of the treated composition samples, in all the incubations at different temperatures and over different periods of time. These results indicated that the amide bond in the transient viscoelastic material was very stable in the buffered composition. ;Example 11;NMR analysis to determine the degree of substitution of the hydrophobic groups in hydrophobically modified hyaluronic acid (HM-HA) compounds; 3-5 mg of a HM-HA material was filled into 4 ml glass bottles. The same bottle was filled with 0.8 ml of water, and the bottle was then vortexed for 5 to 10 seconds. The sample bottle was placed in an oven adjusted to 50°C and heated overnight (15-20 hours) to achieve dissolution. The following day, a hyaluronate lyase enzyme solution (600-900 units/sealed vial, catalog no. H-1136, Sigma Chemical Co.) was prepared by breaking open the sealed vial and adding 0.8 ml of water to the vial containing approx. . 900 units of enzyme (1 unit/ul). 100 µl (0.1 ml) of enzyme solution was then added to the bottle. The bottle was capped and placed in a 37°C oven overnight (15-20 hours). ;The following day, the flask was removed from the oven, and 100 µl (0.1 ml) of deuterium oxide (99.6% atomic % D, catalog no. 42,345-9, Aldrich Chemical Co.) was added to the bottle. After mixing, the solution was transferred to an NMR tube using a disposable glass transfer pipette. The sample was then analyzed to obtain a proton NMR spectrum on a Bruker 600 MHz NMR instrument that could be operated in moisture suppression mode with an accurate integration of peak signals. ;Using the NMR spectrum of the enzyme-treated HM-HA sample, the degree of hydrophobic substitution was calculated from integration values by adding the integral values for the 3 signals that indicated the hydrophobic residue from 0.8 to 1.3 ppm, against the 2 to 4 signals at 2.0-2.1 ppm for the N-acetylmethyl group. ;The three signals between 0.8-1.3 ppm originate from the hydrogen atoms that are bound to C2 to Cn carbon atoms in the hydrophobic group, which contains n carbon atoms. The hyaluro-natlyase enzyme has no interfering signals in the hydrophobic group region or in the N-acetylmethyl signal region. As the N-acetylmethyl group is present on every repeating unit in the HA structure, the degree of hydrophobic substitution can be calculated from the ratio between the integral values for the hydrophobic group and the N-acetylmethyl group. Therefore, the calculation of the degree of substitution of a HM-HA substance with a straight-chain normal alkyl group [-(CH2) n-iCH3] as its hydrophobic substituent with n carbon groups can be given by the equation: ; Example 12; The following example demonstrates the inferior stability of the less preferred viscoelastic materials of the present invention. Compositions that were analogous to the compositions of Examples 1-6, where the viscoelastic material had been replaced with either a 15% dodecyl ester HA sodium salt (about 200 kDa) or a 43% or 52% benzyl ester HA sodium salt (about 200 kDa final, modified viscoelastic material), was prepared in a manner similar to that described in the procedure in Example 7. The compositions were incubated at 4°C, RT and .37°C over 9.5 weeks. The dodecyl or benzyl alcohol (decomposition products of the corresponding hydrophobic ester side chains) was quantified using the GC method from Example 10. After a given incubation period, the samples were mixed with four volumes of acetone, which caused precipitation of the polysaccharide. The precipitated polysaccharide was then centrifuged together, and the supernatant was analyzed by GC for the presence of the appropriate alcohol. ;A complete hydrolysis of the dodecyl or benzyl ester HA side chains would lead to 70 ppm dodecyl alcohol or 400 ppm benzyl alcohol in the supernatant, respectively. The results are listed in table 6. ; As stated above, the hydrolysis of the comparative modified viscoelastic materials was above 1% over various time periods. As it is desirable that the viscoelastic compositions should be stable during storage (i.e. that viscoelastic products should as a rule be stable when stored for 2 years), viscoelastic materials exhibiting the above described hydrolysis rates are considered to be less useful in compositions according to present invention. Example 13 A 3% solution of the benzyl ester of HA with 50% carboxylic acid substitution (about 200 kDa) was prepared in phosphate buffer with sodium chloride and in citrate/acetate buffer with balanced salts. These solutions formed optically clear, viscoelastic gels that could be easily aspirated through a 27 gauge needle. These solutions had low shear viscosities comparable to "Viscoat<®>" or "Provisc<®>" at 25°C (ie about 200 Pa-s), and were shear-thinning like "Provisc<®>" or "Viscoat <®>" at 25°C. These solutions showed a significantly reduced viscosity from approx. 200 Pa-s at operating temperature (25°C) to 20 Pa-s at body temperature (37°C). Example 14 A 1% solution of the dodecyl ester of HA with 14.3% carboxylic acid substitution (about 200 kDa) was prepared in citrate/acetate buffer with balanced salts to form a clear, viscoelastic solution. This solution exhibited a comparable rheological profile to "Provisc<®>" or "Viscoat<®>". The viscosity at 25°C and at shear rates below 0.085/s was approx. 90 Pa-s. The shear thinning started at 0.24/s with a viscosity of 75 Pa-s. At 5.4/s the viscosity had dropped to approx. 16 Pa-s. At 31°C, the low shear viscosity was only approx. 45 Pa-s. At a constant shear stress of 2.89 Pa, the viscosity of this formulation fell from approx. 100 Pa-s at 25°C to approx. 25 Pa-s at 37°C. Example 15 A 0.75% solution of the dodecyl ester of HA with 14.3% carboxylic acid substitution (about 200 kDa) was prepared in eitrate/acetate buffer with balanced salts to form a clear, viscoelastic solution. This solution exhibited a low shear viscosity of approx. 25 Pa-s at 25°C, and was shear-thinned to below 0.1 Pa-s at 534/s. This formulation also showed a decreasing viscosity at constant shear stress (1.1 Pa) from approx. 25 Pa-s at 25°C to approx. 5 Pa-s at 37°C. ;Example 16;A 2% solution of the dodecyl ester of HA with 14.3% carboxylic acid substitution (about 200 kDa) was prepared in citrate/acetate buffer with balanced salts to form a clear, thick solution. This solution (approx. 2 cc) was autoclaved at 125°C for approx. 20 minute treatment duration, and was cooled with slow exhaust. After cooling to room temperature, the formulation retained sufficient viscosity to provide a useful viscoelastic gel. ;Example 17;A 5% solution of the hexadecyl ether of carboxymethylcellulose (containing hexadecyl units ether-linked to 5% of the repeating monosaccharide units and of about 100 kDa) was prepared in phosphate buffer with sodium chloride. The solution was clear and qualitatively formed a viscous gel. ;Example 18;A solution of a 1.0 wt% 20% dodecylamide of HA, sodium salt with 3% chondroitin sulfate, was prepared in PBS by slow dissolution at 50°C over two days. Another sample, containing only 1.0 wt% 20% dodecylamide of HA sodium salt, was likewise prepared in PBS by slow dissolution at 50°C for two days. After dissolution, the samples were transferred to individual 10 mL syringes and subjected to 100 passes through a 2-hub coupling to another empty syringe to provide adequate mixing. The samples were centrifuged to remove air bubbles, and aspirated through a 27 gauge needle into the sample plate of a CS-10 Constant Stress Rheometer from Bohlin. Rheological analysis was performed to provide plots of viscosity versus shear rate at 25°C for both samples. Both samples gave apparent viscosity values of approx. 90 Pa-s in the low-shear plateau region of the plot of viscosity versus shear rate. ;Example 19;The following is a description of the IOP peak model. IOP peak model: The IOP peak model uses (1) a perfusion device, pump and pressure transducer/recording device as depicted diagrammatically in fig. 7; (2) perfusion medium; (3) dissected human eyes; and (4) the viscoelastic material(s) to be tested. ;1. Perfusion medium; The perfusion medium used in the IOP peak model is prepared by adding 5 ml of a penicillin-streptomycin solution (10,000 units/ml penicillin (base) from penicillin G and 10,000 ug/ml streptomycin (base) from streptomycin -sulfate) and 0.85 ml gentamicin solution (10 mg/ml) to 500 ml cell culture medium (Dulbecco's modified Eagle medium, low glucose, with L-alanyl-L-glutamine and pyruvate (Life Technologies, Grand Island, NY)). The perfusion medium is then filtered using a 500 ml sterile filter unit (0.2 (.im pore size) and stored at 4°C (brought to 37°C before use). ;2 . Preparation of the eye; Cadaver eyes useful in IOP peak -the model, must: i) not be older than 24-36 hours post-mortem when they are prepared for use in the model; ii) stored in the form of whole eyes in moist chambers; iii) be free of HIV, hepatitis or other infectious agents; and iv) not having undergone ocular surgery such as glaucoma filtration, scleral buckling implantation, or IOL implantation. The anterior segment 7 (see fig. 10) of a human eye is prepared by the following dissection method: Carefully remove excess muscle or connective tissue from the eye using straight, small scissors (Katena no. K4-7440) and place the eye in a container containing a povidone-iodine solution (1% free iodine) at 25°C for approx. 2 minutes. The eye is then removed from the iodine solution, rinsed thoroughly with saline solution and positioned so that the cornea 3 is centered on top (see Fig. 9a). Referring to fig. 9a and 9b, the sclera 5 is then incised (using a sterile ophthalmic bent knife (Alcon no. 8065-940001) with 24 evenly spaced cuts 9 extending radially from the limbus towards the ora serrata (where the cuts are not deeper than 50% of sclera and each cut is approximately 5 mm long) to open the episcleral veins and provide an outlet route for the perfusion medium. Referring to Fig. 9b, the eyeball is then cut into two halves along the horizontal plane 11 approximately halfway between the equatorial plane 13 and the scleral plane 15. The anterior (upper) half of the eye is separated from the posterior (lower) half, which is discarded.The anterior half is turned so that the cornea is downward, and residual fluid is then carefully removed from the anterior half using a Graefe pin. set (Katena No. K5-4821). The zonules are then cut with Wescott scissors (Katena No. K4-4100), and the lens is removed from the anterior segment using the Graefe forceps. A dressing forceps , Catena no. K5-4010) is then used for to remove the iris, and the choriodea is cut peripherally along the ora seratta with the Wescott scissors. Any remaining pigment inside the sclera is then removed with the fine cleaning tweezers. The remaining anterior segment 7 is then rinsed twice with perfusion medium to wash away pigments, tissue remnants or other debris. ;3. Perfusion apparatus; The perfusion apparatus used in the IOP peak model is a modified version of what is described in the perfusion systems of Johnson and Tschumper as well as Clark et al. (Johnson and Tschumper, "Human trabecular meshwork organ culture: a new method", Invest. Ophthalmol. Vis. Sei., 28: 945-953 (1987); and Clarke et al., "Dexamethasone-Induced Ocular Hypertension in Perfusion-Cultured Human Eyes", Invest. Ophthalmol. Vis. Sei., 36 (2): 478-489 (1995)). The significant modifications to the previous systems are a reduction of the chamber volume from approx. 0.8-1.0 ml to approx. 0.5-0.6 ml to achieve a better approximation to the volume of the pseudophakic human anterior segment, and that the chamber is turned upside down during perfusion. The volume reduction is achieved by means of a projecting island on the chamber's platform, which reduces the space within the vaulting of the anterior segment and which is to prevent or reduce a stagnation of the viscoelastic solution in the posterior dead space, i.e. behind the trabecular network. Turning the chamber upside down (compared to previous systems) during the perfusion is believed to prevent an occurrence of stagnation of the viscoelastic material in the corneal cavity, as such a viscoelastic material is believed to mix well with the perfusant coming out of the tip -known island in the direction of this cavity. The perfusion apparatus 1 is illustrated in fig. 7, 8 and 10. The device 1 consists of a base 2, a cylinder 4, an island 6, an o-ring 8, a plurality of screws 10 and a cover 12. In use, the device 1 also comprises a front segment 7. ;The base 2 is shaped like a round disc with top 22, bottom 24 and side 26, and contains channels 14 and 16, the platform ;18 and threads 19, which are shaped and dimensioned to receive screws 10. The channel 14 communicates with the opening 28 in the side 26 and the opening 20 in the eye 6. Channel 16 communicates with the opening 30 in the side 26 and the opening 32 in the platform 18. The channels 14 and 16 are shaped and dimensioned so that they provide an accurate current (channel 14) and an accurate pressure measurement (channel 16) of perfusion medium, to and from the apparatus 1. The opening 28 is shaped and dimensioned so that it takes up a fitting (to be connected to the infusion tube 29), and the opening 30 is also shaped and dimensioned so that it takes up a fitting (to be connected to a converter pipe 31). The fittings are standard connectors known in the art to be useful for receiving pipes or other cylindrical pipes. The platform 18 projects from the base 2, has a side 34 and is conically shaped and dimensioned so that it takes up a front segment 7. The eye 6 protrudes from the center of the platform 18. Referring to fig. 8 and 10, the cylinder 4 is coaxially and permanently located on the top 22 of the substrate 2, and extends flat from there. The eye 6 has an opening 20, contains a portion of the channel 14 and extends from the platform 18. The O-ring 8 has an annular concave inner edge 36 and a plurality of holes 38 which are sized and shaped to receive screws 10 through the o- the ring 8. The edge 36 is dimensioned and shaped so that when the device 1 is put into operation, the compression of the o-ring 8 against the base 2 will squeeze the periphery of the front segment 7 between the edge 36 and the side 34 of the platform 18 and thus form the anterior chamber 42. As described above, the volume of the anterior chamber 42 has been designed by the present inventors to be approximately equal to the combined volume of the anterior chamber and the crystalline lens of a human eye (generally about 0.5-0.6 ml). As can be seen from fig. 8 and 10, the lid 12 is shaped and dimensioned so that it takes up a portion of the cylinder 4 and forms a closed space 40. The preferred perfusion apparatus for the IOP peak model utilizes a polysulfone base 2, a polysulfone island 6 , a polysulfone o-ring 8, nylon screws 10, a transparent polysulfone cylinder 4, medical steel channels 14 and 16, and a transparent polystyrene lid 12. 4. Assembling and preparing the perfusion apparatus: Before use, take the apparatus 1 apart, and the individual parts are autoclaved or cold sterilized and then soaked in a laminar flow chamber with a disinfectant sporicidin solution (50 ml/l water), followed by rinsing overnight in sterile deionized water. Referring to fig. 7 and 10, perfusion medium is fed to the pump, which in turn is connected to an infusion tube 29, which will infuse perfusion medium through channel 14 and into chamber 42; and the transducer tube 31 is connected to a calibrated pressure transducer and recording device which has the ability to register the pressure in the chamber 42. The apparatus 1 is then reassembled by first connecting fittings located at the openings 28 and 30 to the infusion and transducer tube respectively. The apparatus 1 is then placed with the top 22 facing upwards. The anterior segment 7 is placed on platform 18 with the cornea facing upwards. A gentle stream of perfusion medium is then supplied through a syringe through channel 16, to place the segment 7 properly on the platform 18. The O-ring 8 (which is approximately 3.8 cm in diameter, outer circumference, and 1.8-1, 9 cm in inner diameter) is then placed over the segment 7. It is important that the o-ring 8 fits well on the segment 7, to avoid leaks (an o-ring 8 with a slightly different diameter can be used to make it fit better) . Screws 10 are introduced through the holes 38 and into the threads 19, and are screwed in evenly to ensure that the o-ring 8 sits evenly. As the o-ring 8 is attached to the periphery of the segment 7, the flow through the channel 16 should be eased, so that too much pressure is not applied to the segment 7 after it has been placed. The screws 10 are turned against the substrate 2, so that the periphery of the segment 7 is pressed hard together between the platform 18 and the o-ring 8, but not so hard that the segment 7 cracks. When using syringes, perfusion medium is then pushed through channel 14 while perfusion medium is simultaneously drawn out of channel 16 through the opening 30, holding the substrate 2 at an angle so that any bubbles present will flow out of the chamber 42 through channel 16. After the bubbles have been removed , the channels 14 and 16 are closed for the flow of perfusion medium. The apparatus 1 is then straightened again with the top 22 facing upwards. The lid 12 is then placed over the cylinder 4, whereby a space 40 is formed. The apparatus 1 is then turned upside down so that the bottom 24 faces upwards, and placed in a tissue culture incubator (Nuaire) while maintaining a humidified atmosphere (5% C02 / 95% air) at 37°C. The converter tube 31 and the infusion tube 29 should be placed against the seal of the incubator door, so that they are not damaged or wrinkled when the door is closed. The pressure transducer should be kept level with device 1. In this configuration, device 1 is now ready for use in the IOP peak model. ;5. First perfusion:; The perfusion tube is opened, and the pump is put into operation (position "6" for Harvard Model No. 944) so that the perfusion medium flows freely through the opening 28 and the channel 14. The pump is allowed to run until the pressure rises to approx. 5-10 mm Hg, the pump speed is then reduced to approx. 2 u.l/min (position "12"). Segment 7 is perfused for up to approx. 24 hours before injection of the viscoelastic candidate material. If no stable baseline is achieved at a pressure between 10-40 mm Hg within 24 hours, the flow rate can be adjusted repeatedly for a perfusion volume of 2-3 ml each time, until a stable baseline IOP is achieved . If the problem is not resolved in another 24 hours, and subsequent adjustment of the flow rate and flush step has not resolved the problem within 48 hours, the presegment 7 must be considered unreliable and the perfusion should be terminated. 6. Injection and perfusion of viscoelastic material: When a perfused foresegment 7 has generated a stable output IOP between 10-40 mm Hg over a period of no less than 4 hours (perfusion rate between 1.75-2.05 ;ul/min ), it is ready for investigations of IOP peaks. Usually such a point is reached 24 hours after the first perfusion. The model is first validated by injecting a positive control. The positive control is 0.5 ml of diluted sodium hyaluronate (approximately 750 kDa available from Lifecore Biomedical, Inc., Chaska, MN), which is prepared by diluting 1 part 3.5% HA in buffer solution with 9 parts of the same buffer solution , where each 1 ml buffer solution contains approx. 0.45 mg sodium dihydrogen phosphate hydrate, 2.00 mg disodium hydrogen phosphate, 4.3 mg sodium chloride (with water for injection, USP quality, q.s.) and has a neutral pH value. The positive control of 0.5 ml of diluted HA (0.35%) is injected into a tubing loop of similar volume connected to the multi-valve assembly 33 on the perfusion tube 29, and the multi-valve assembly 33 is repositioned to allow the entire sample volume to be flushed into the perfusion apparatus 1. Thus, the injection rate is determined by the perfusion rate. The IOP value is continuously monitored and recorded. Any IOP peak above the baseline IOP value is observed and recorded. If the positive control results in an IOP peak that is between 20-80 mm Hg above baseline within 24 hours of injection, the model is considered validated and can be used to test transient viscoelastic candidate materials. ;Generally, samples of transient viscoelastic materials can be injected 2 times into a single foresegment, at 1-day intervals (with the first injection being the injection of the positive control). Samples of viscoelastic material should be diluted to 1/10 of the original concentration using the same buffer solution used to prepare the control sample. A stable and acceptable baseline IOP value should be achieved before each new injection, as evidenced by a lowering from an IOP peak generated by a previous viscoelastic test. If the baseline IOP value is not achieved within the range of 10-40 mm Hg within 1 day, no further perfusion into a given foresegment should be initiated. As noted above, a transient viscoelastic material of the present invention (ie, causing little or no IOP peak) will exhibit a mean peak that is 10 mm Hg or less above baseline. ;Example 20;A transient viscoelastic material of the present invention, namely AL-12488, 43% substituted benzyl ester-modified HA (about 200 kDa) was tested in the IOP peak model described above and compared to the positive control (reference) and 200 kDa HA from Fidia. The results of the survey are shown graphically in fig. 11. The arrows refer to the different injections. Injections 1 and 4 were 0.35% positive control HA, injection 2 was 0.35% unmodified HA from Fidia, and injection 3 was 0.35% AL-12488. All the injection samples had a volume of 0.5 ml. The stars show the individual IOP peaks that were caused by the injections. Only the transient viscoelastic material (AL-12488) can be said to exhibit little or no IOP peak, as the peak observed for this material in the IOP peak model is not above, and in fact considerably below, approx. 10 mm Hg more than the baseline IOP value. Those skilled in the art will appreciate that the suitability of a given transient viscoelastic material for a particular step in a surgical procedure will depend on such things as the concentration of the viscoelastic material, the average molecular weight, the viscosity, the pseudoplasticity, the elasticity, the stiffness, the tackiness (coatability), the cohesiveness , the molecular charge and the osmolality in solution. The suitability of the viscoelastic material will also depend on the function(s) that the viscoelastic material is to fulfill and the surgical technique used by the surgeon. A suitable buffer system (eg sodium phosphate, sodium acetate or sodium borate) can be added to the compositions to prevent a pH change under storage conditions. According to all or a considerable part of the transient viscoelastic material according to the present invention. can be left in the eye after surgery, these viscoelastic materials are uniformly adapted to serve the two roles of viscosurgical tool and drug delivery device. Ophthalmic drugs which are suitable for use in the compositions according to the present invention include, but are not limited to: anti-glaucoma drugs, such as beta-blockers including timolol, betaxolol, levobetaxolol, carteolol, miotics including pilocarpine, carbonic anhydrase inhibitors tors, prostaglandins, serotonergics, muscarinics, dopaminergic agonists, adrenergic agonists including apraclonidine and brimonidine; anti-infective agents including quinolones such as ciprofloxacin, and aminoglycosides such as tobramycin and gentamicin; non-steroidal and steroidal anti-inflammatory agents, such as suprofen, diclofenac, ketorolac, rimexolone and tetrahydrocortisol; growth factors such as EGF; immunosuppressive agents; and anti-allergic agents including olopatadine. The ophthalmic drug may be in the form of a pharmaceutically acceptable salt, such as timolol maleate, brimonidine tartrate or diclofenac sodium. Compositions according to the present invention may also include combinations of ophthalmic drugs, such as combinations of (i) a beta-blocker selected from the group comprising betaxolol and timolol, and (ii) a prostaglandin selected from the group comprising latanoprost; 15-keto-latanoprost; fluprostenol isopropyl ester (especially IR- ;[la(Z),2p(1£, 3R*) , 3a,5a]-7-[3,5-dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl) phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethyl ester); and isopropyl-[2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3- furanyl]-4-heptenoate.

If a pharmaceutical agent is added to the transient viscoelastic materials, these agents may have a limited solubility in water, and may thus require the presence of a surfactant or other suitable co-solvent in the composition. Such co-solvents typically include: polyethoxylated castor oils, Polysorbate 20, 60 and 80; "Pluronic<®>" F-68, F-84 and P-103 (BASF Corp., Parsippany NJ, USA); cyclodextrin; or other means known to the person skilled in the art. Such co-solvents are usually used in an amount of from 0.01 to 2% by weight. It may also be desirable to add a pharmaceutically acceptable dye to the viscoelastic material to improve visualization of the viscoelastic material during surgery and/or to stain the ocular tissue (especially the capsular bag during capsulorhexis in cataract surgery) to achieve a better visualization of such tissue. Use of such dyes in conventional viscoelastic materials is described in WO 99/58160. Preferred dyes include "Trypan Blue", "Trypan Red", "Brilliant Crysyl Blue" and "Indo Cyanine Green". The concentration of the dye in the viscoelastic solution will preferably be between approx. 0.001 and 2% by weight, and most preferably between approx. 0.01 and 0.1% by weight. However, the person skilled in the art will understand that any such additive (pharmaceutical agents, co-solvents or dyes) can only be used to the extent that they have no harmful effect on the viscoelastic properties of the compositions according to the present invention.

The methods according to the present invention can also include the use of different viscoelastic materials which have different adhesive or cohesive properties. The person skilled in the art will understand that the compositions according to the present invention can be used by the surgeon in various surgical procedures.

Given the advantages of each type of viscoelastic material, the surgeon may use different viscoelastic compositions of the present invention in one and the same surgical procedure. Although use of the transient viscoelastic materials of the present invention has not previously been described for use in surgery, US Patent No. 5,273,056 (McLaughlin et al.) describes methods utilizing compositions using viscoelastic materials with different viscoelastic properties during a given ocular operation, and the entire content of this publication is hereby incorporated by reference.

E.g. is it for parts of surgical procedures including phacoemulsification and/or irrigation/suction, e.g. cataract surgery, it is generally preferable to use a viscoelastic material which has relatively better adhesiveness and relatively less cohesive ability. Such viscoelastic materials are referred to herein as "sticky" materials. The cohesiveness of a viscoelastic material in solution is assumed to be at least partially dependent on the average molecular weight of this material. In a given concentration, the greater the cohesiveness, the greater the molecular weight. Sections of surgical procedures that require the manipulation of sensitive tissue will generally be better served by viscoelastic materials that have relatively stronger cohesive properties and relatively lower adhesive properties. Such materials are referred to herein as "cohesive" materials. For cohesive materials such as these, which are used primarily for tissue manipulation or preservation purposes as opposed to protective purposes, a functionally desirable viscosity would be a viscosity sufficient to enable the surgeon to use such materials as soft tools to manipulate or support the relevant tissue during the surgical step(s) performed.

For other viscoelastic materials, which are used primarily for protective purposes ("sticky" materials) as opposed to tissue manipulation purposes, a functionally desirable viscosity would be a viscosity sufficient for a protective layer of such material to adhere to the tissue or tissues in question relevant cells during the surgical step(s) to be performed. Such a viscosity will usually be from about. 3,000 eps to approx. 60,000 eps (at a shear rate of 2 sec"<1>and 25°C), and would preferably be about 40,000 eps. Such adhesive materials can provide the above-described protective function, but are not prone to accidental removal, which could endangering the sensitive tissue to be protected. Worse, this same property makes it problematic for surgeons to absorb such adhesive viscoelastic materials after surgery (as is recommended for all such commercially available products in cataract surgery), and may lead to for the coated tissues to be exposed to trauma during the removal procedure. A significant advantage of the transient viscoelastic materials according to the present invention is that they can be left at the surgical site after surgery, whereby an unnecessary trauma to the affected soft tissues can be avoided.

Preferred methods according to the present invention will make use of different viscoelastic materials in a given surgical procedure, where at least one of these viscoelastic materials is a transient viscoelastic material. In a most preferred embodiment of the invention, a transient viscoelastic material that has superior adhesive properties is used in cataract surgery, and after the surgery is completed, all or part of the transient viscoelastic material is left in situ and causes little or no IOP peak.

The invention has been described with reference to certain preferred embodiments. However, it should be understood that it may be practiced in other specific forms or variations thereof without deviating from its idea or essential characteristics. The embodiments described above shall therefore be considered to be illustrative in all respects, and not limiting, as the scope of the invention is stated in the attached claims rather than in the preceding description.

Claims (1)

1. A sterile, non-inflammatory viscoelastic composition comprising a polymeric material in aqueous solution, wherein the composition exhibits a zero-shear viscosity of at least 1 Pa-s at 25°C, and wherein the viscoelastic composition exhibits little or no IOP peak when tested in a validated IOP peak model. 2. Composition according to claim 1, where the polymeric material is selected from the group comprising: hydrophobically modified polysaccharides or mucopolysaccharides (with or without surfactants); dialyzed polyampholytes or dialyzed mixtures of oppositely charged polyelectrolytes; mixtures of polysaccharides or mucopolysaccharides with cationic hydrophilic polymers; polysaccharides and hydrophilic synthetic polymers with temperature-dependent conformational transitions; and combinations thereof. 3. Composition according to claim 2, where the solution exhibits a zero-shear viscosity at 25°C from approx. 5 to approx. 10,000 Pa-s, and a viscosity factor approx. 1,000 to approx. 20,000. 4. Composition according to claim 3, wherein the polymeric material is a hydrophobically modified polysaccharide selected from the group comprising HA amides, HA esters, HA amines, HA ethers, HA thioethers, HA alkyls and combinations thereof. 5. Composition according to claim 4, where the polysaccharide is an HA-amide selected from the group comprising octylamide-HA, dodecylamide-HA and hexadecylamide-HA. 6. Procedure for performing surgery on an eye, comprising: (a) providing a surgical opening in the eye to enable access to the interior of the eye; (b) introducing a viscoelastic composition according to claim 1 through the surgical opening into the interior of the eye; and (c) close the surgical opening. 7. Method according to claim 6, where the viscoelastic composition has a zero-shear viscosity at 25°C from approx. 5 to approx. 10,000 Pa-s, and where this viscosity is reduced by at least 50% when the transient viscoelastic material undergoes a temperature change from approx. 25°C to approx. 37°C. 8. Method according to claim 7, where the surgical opening is closed without a prior exogenous removal of the viscoelastic composition. 9. Method of performing surgery on an eye without any significant postoperative intraocular pressure peak, comprising: (a) introducing into the eye a first therapeutically effective amount of a transient viscoelastic material, wherein the transient viscoelastic material is a sterile, non-inflammatory, aqueous solution having a zero-shear viscosity of at least 5 Pa-s at 25°C , and where the transient viscoelastic material exhibits little or no IOP peak when tested in a validated IOP peak model; and (b) leaving a second therapeutically effective amount of the transient viscoelastic material in the eye after completion of surgery; wherein the first and second therapeutically effective amounts of the transient viscoelastic material may be the same or different. 10. Method according to claim 9, wherein the first therapeutically effective amount of a transient viscoelastic material is selected from the group comprising: a tissue protective effective amount, a tissue manipulative effective amount and a drug delivery effective amount of the transient viscoelastic elastic material; and wherein the second therapeutically effective amount of the transient viscoelastic material is selected from the group comprising: a tissue protective effective amount and a drug delivery effective amount of the transient viscoelastic material. 11. Method according to claim 10, wherein the transient viscoelastic material comprises hydrophobically modified HA. 12. Method according to claim 11, where the hydrophobically modified HA is a HA and is selected from the group comprising octylamide-HA, dodecylamide-HA and hexadecylamide-HA. 13. Method according to claim 12, wherein the surgery is cataract surgery. 14. Method of protecting or stabilizing ocular tissue in an eye during surgery thereon, comprising introducing into the eye a protective or stabilizing effective amount of a sterile, non-inflammatory viscoelastic composition, wherein the viscoelastic composition exhibits little or no IOP peak when tested in a validated IOP peak model. 15. A sterile, non-inflammatory transient viscoelastic composition comprising a hydrophobically modified polysaccharide in an aqueous solution, wherein the solution exhibits a zero-shear viscosity of at least 1 Pa-s at 25°C, and wherein the zero-shear viscosity of the solution is decreased by at least 50% when the solution undergoes a temperature change from approx. 25°C to approx. 37°C. 16. Composition according to claim 15, wherein the solution exhibits a zero-shear viscosity at 25°C from approx. 5 to approx. 10,000 Pa-s and a viscosity factor from. about. 1,000 to approx. 20,000. 17. Composition according to claim 16, wherein the hydrophobically modified polysaccharide is selected from the group comprising HA amides, HA esters, HA amines, HA ethers, HA thioethers and HA alkyls and mixtures thereof. 18. Composition according to claim 17, wherein the polysaccharide is an HA-amide selected from the group comprising octylamide-HA, dodecylamide-HA and hexadecylamide-HA. 19. Procedure for performing surgery on an eye, comprising: (a) making a surgical opening in the eye to provide access to the interior of the eye; (b) introducing a transient viscoelastic material through the surgical opening into the interior of the eye; and (c) close the surgical opening. 20. Method according to claim 19, wherein the transient viscoelastic material has a zero-shear viscosity at 25°C from approx. 5 to approx. 10,000 Pa-s, and where this viscosity is reduced by at least 50% when the transient viscoelastic material undergoes a temperature change from approx. 25°C to approx. 37°C. 21. Method according to claim 20, wherein the surgical opening is closed without any prior exogenous removal of the transient viscoelastic material. 22. Method of performing surgery on an eye without any significant postoperative intraocular pressure peak, comprising: (a) introducing into the eye a first therapeutically effective amount of a transient viscoelastic material, wherein the transient viscoelastic material is a sterile, non-inflammatory, aqueous solution having a zero-shear viscosity of at least 5 Pa-s at 25° C, and where this viscosity is reduced by at least 50% when the transient viscoelastic material undergoes a temperature change from approx. 25°C to approx. 37°C; and (b) allowing a second therapeutically effective amount of the transient viscoelastic material to remain in the eye after surgery is completed; wherein the first and second therapeutically effective amounts of the transient viscoelastic material may be the same or different. 23. Method according to claim 22, wherein the first therapeutically effective amount of a transient viscoelastic material is selected from the group comprising: a tissue protective effective amount, a tissue manipulative effective amount and a drug delivery effective amount of the transient viscoelastic material; and wherein the second therapeutically effective amount of the transient viscoelastic material is selected from the group comprising: a tissue protective effective amount and a drug delivery effective amount of the transient viscoelastic material. 24. Method according to claim 23, wherein the transient viscoelastic material comprises hydrophobically modified HA. 25. Method according to claim 24, wherein the hydrophobically modified HA is a HA and is selected from the group comprising octylamide-HA, dodecylamide-HA and hexadecylamide-HA. 26. Method according to claim 25, where the surgery is cataract surgery.