WO2000035432A2

WO2000035432A2 - Improved viscoelastic compositions and methods of use

Info

Publication number: WO2000035432A2
Application number: PCT/US1999/029442
Authority: WO
Inventors: Mandar V. Shah; Uday Doshi; Kerry L. Markwardt
Original assignee: Alcon Laboratories, Inc.
Priority date: 1998-12-17
Filing date: 1999-12-10
Publication date: 2000-06-22
Also published as: AU2175500A; WO2000035432A3

Abstract

Compositions and methods for treating mammalian tissues are disclosed. The compositions are improved stability, viscoelastic compositions comprising physiological antioxidants, bifunctional compounds having an anti-inflammatory and anti-oxidant moiety covalently linked by an amide or ester bond, in a viscoelastic vehicle. The methods are particularly useful in the prevention or treatment of inflammatory and proliferative events incident to ocular surgery.

Description

IMPROVED VISCOELASTIC COMPOSITIONS AND METHODS OF USE

Background of the Invention

The present invention is directed to improved stability viscoelastic compositions and

methods of use. More specifically, the present invention is directed to stable viscoelastic compositions containing a bifunctional compound (i.e., a compound comprised of antioxidant and anti-inflammatory moieties) and an amount of physiological antioxidant (e.g., ascorbate) to stabilize the bifunctional compound. The present invention is also directed to various

methods of using the compositions of the present invention in the treatment of ocular

inflammation associated with ophthalmic disease and ophthalmic surgery.

Ocular surgery can result in various post-surgical complications to the eye. Such complications generally include: 1) loss of vascular blood barrier function; 2) neutrophil accumulation; 3) tissue edema including conjunctiva swelling, conjunctiva congestion and

corneal haze; 4) cataract formation; 5) cellular proliferative disorders including neovascularizations, fibrosis and posterior capsule opacification; and 6) loss of membrane

integrity including decrease in docosahexaenoic acid levels in membrane phospholipids.

Cataracts are opacities of the ocular lens which generally arise in the elderly. In order

to improve eyesight, the cataractous lens is removed and an intraocular lens is inserted into

the capsular bag. In order to maximize the procedure and post-surgical recovery, viscoelastic materials are injected in the anterior chamber and capsular bag to prevent collapse of the

anterior chamber and to protect tissue from damage resulting from physical manipulation.

Various inflammatory responses and tissue damage, however, may still occur from such surgeries, as described above. There is a need, therefore, for the provision of improved viscoelastic compositions and methods which aid in the amelioration of inflammation, tissue damage and trauma-induced complications resulting from anterior segment surgery (e.g.,

cataract surgery and trabeculectomy).

Trabeculectomy, i.e., glaucoma filtration surgery, involves the surgical creation of a fistula with a conjunctival flap, which allows the direct drainage of aqueous humor from the anterior chamber into the conjunctival tissue. This procedure is used as an alternative to drug

therapy, and allows for an increase in outflow of aqueous humor, thereby lowering the

elevated intraocular pressure associated with glaucoma. In order to maintain a deep chamber

and enhance visualization during the surgery, viscoelastic compositions have been injected into the anterior chamber of the eye. Inflammatory responses resulting from the surgery, however, may cause complications. For example, many patients exposed to prior inflammatory episodes (e.g., uveitis, cataract extraction) have an increased incidence of "bleb" failure due to fibroplasia. With such complications, the filtration bleb becomes scarred or heals over so that aqueous drainage can no longer occur. Thus, a need exists for the provision of improved viscoelastic compositions which further decrease the inflammatory

response, cellular damage, and proliferation resulting from glaucoma filtration surgery,

permitting an increased longevity of the filtration bleb following surgery.

Vitrectomy surgery can also induce a variety of post-surgical complications. Many of these complications are further potentiated in diabetic patients who are at risk for many ocular

pathologies. Due to the severity of the surgical procedure, the posterior segment surgery

process can cause extensive tissue damage at both the acute and chronic phases of the

recovery. Tissue edema generally occurs during the post-surgical acute phase. This is caused by breakdown of the blood aqueous and blood retinal barrier functions resulting in sustained vascular permeability and accumulation of plasma constituents in the ocular compartments following the surgical trauma. Ocular neovascularization may occur during the post-surgical chronic phase. The presence of elevated inflammatory and serum factors induce cell

proliferation during the normal wound healing process. Slitlamp clinical examinations at 24

hours have indicated extensive anterior chamber flare and cell influx, conjunctiva congestion and swelling (with discharge), iritis, and corneal haze. See for example, Kreiger, A.E., Wound Complications In Pars Plana Vitrectomy, Retina, volume 13, No. 4, pages 335-344 (1993); Cherfan, G.M., et al., Nuclear Sclerotic Cataract After Vitrectomy for Idiopathic

Epiretinal Membranes Causing Macular Pucker, American Journal Of Ophthalmology, volume 1 11, pages 434-438 (1991); Thompson, J.T., et al., Progression of Nuclear Sclerosis and Long-term Visual Results of Vitrectomy With Transforming Growth Factor Beta-2 for Macular Holes, American Journal Of Ophthalmology, volume 119, pages 48-54 (1995) and

Dobbs, R.E., et al., Evaluation Of Lens Changes In Idiopathic Epiretinal Membrane, volume

5, Nos. 1 & 2, pages 143-148 (1988).

The chronic phase of the postsurgical period is characterized by more severe complications that can necessitate additional surgery. These include an incidence of recurrent retinal detachment, epiretinal proliferation, neovascular glaucoma, corneal problems, vitreous

hemorrhage, cystoid macular edema, and occurrence of cataract formation within six months

of surgery. While various surgical irrigating and viscoelastic compositions are employed, the frequency of above-described complications still needs to be lessened by facilitating the

recovery of vascular leakage and limiting the duration of the cellular proliferative response.

Therefore, a need exists to improve the current effectiveness of viscoelastic compositions

used in vitrectomy surgery. United States Patent No. 5,480,914 (Meadows) describes the use of non-aqueous

perfluorocarbon carriers to deliver various compounds to the eye. United States Patent No. 5,166,331 (della Velle et al.) discloses the use of hyaluronic acid compositions to deliver various compounds to the eye. Neither of these references, however, disclose the

compositions and methods of the present invention.

United States Patent No. 5,811,453 (Yanni et al.) discloses viscoelastic compositions containing cytoprotective bifunctional compounds and methods of use in treating mammalian tissues. The bifunctional compounds of the Yanni et al. patent, however, are believed to be

inherently unstable over time in aqueous solutions. Thus, those compositions may possess a

limited shelf-life due to the potential instability of the bifunctional compounds contained therein. The present invention improves on those viscoelastic compositions by improving the shelf-life stability of the compositions.

Summary of Invention

The present invention is directed to improved viscoelastic compositions and methods of use. The viscoelastic compositions comprise particular bifunctional compounds (i.e.,

compounds comprised of antioxidant and anti-inflammatory moieties), physiological

antioxidants as stabilizers of the bifunctional compounds and viscoelastic agents.

Due to the inherent sensitivity of these bifunctional compounds to oxidation, previous viscoelastic compositions containing these bifunctional compounds may only provide limited

shelf-life. The compositions of the present invention have been formulated to stabilize the

bifunctional compounds, and hence improve the shelf-life of the compositions. It is believed that the presence of physiological antioxidants stabilizes the bifunctional compositions while not interfering with the antiinflammatory, antioxidant and antiproliferative properties of the

bifunctional compounds and, hence, the cytoprotective efficacy of the compositions. The viscoelastic agents contained in the compositions include, but limited to, sodium hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose ("HPMC"), other naturally occurring or synthetic molecules possessing viscoelastic properties, and combinations thereof.

The compositions are useful in surgical applications. The compositions are

particularly well suited for ophthalmic surgery. In general, the compositions of the present invention may be employed for the treatment of inflammatory conditions or other tissue or cellular disorders arising from surgery.

Detailed Description of Invention

The viscoelastic compositions of the present invention comprise one or more viscoelastic agents, one or more physiological stabilizing agents and one or more bifunctional

compounds of the following formula (I):

A-X-(CH₂)_n-Y-(CH₂)_m-Z (I) wherein:

A is an non-steroidal anti-inflammatory agent ("NSAIA") originally having a

carboxylic acid;

A-X is an ester or amide linkage derived from the carboxylic acid moiety of the

NSAIA, wherein X is O or NR;

R is H, C,-C₆ alkyl or C₃-C₆ cycloalkyl;

Y, if present, is O, NR, C(R)₂ , CH(OH) or S(O)_n. ; n is 2 to 4 and m is 1 to 4 when Y is O, NR, or S(O)_n. ; n is 0 to 4 and m is 0 to 4 when Y is C(R)₂ or is not present;

n is 1 to 4 and m is 0 to 4 when Y is CH(OH);

n' is 0 to 2; and

Z is:

wherein:

R' is H, C(O)R, C(O)N(R)₂, PO₃ ^" , or SO₃ ^" ; and

R" is H or C,-C₆ alkyl.

The bifunctional compounds of the present invention also include various stereoisomers or

racemic mixtures of any of the compounds contemplated within formula (I), and

pharmaceutically acceptable salts of the compounds of formula (I).

The bifunctional compounds of the present invention contain a non-steroidal anti-

inflammatory agent, "A", originally having a carboxylic acid moiety. A number of chemical

classes of non-steroidal anti-inflammatory agents have been identified. The following text,

the entire contents of which are incorporated herein by reference to the extent it refers to NSAIAs having a carboxylic acid, may be referred to for various NSAIA chemical classes:

CRC Handbook of Eicosanoids: Prostaglandins, and Related Lipids, Volume II, Drugs Acting Via the Eicosanoids, pages 59-133, CRC Press, Boca Raton, FL (1989). The NSAIA may be selected, therefore, from a variety of chemical classes including, but not limited to, fenamic acids, such as flufenamic acid, niflumic acid and mefenamic acid; indoles, such as indomethacin, sulindac and tolmetin; phenylalkanoic acids, such as suprofen, ketorolac,

flurbiprofen, ibuprofen and diclofenac. Further examples of NSAIAs are listed below:

loxoprofen tolfenamic acid indoprofen pirprofen clidanac fenoprofen naproxen fenclorac meclofenamate benoxaprofen carprofen isofezolac aceloferac fenbufen etodolic acid fleclozic acid amfenac efenamic acid bromfenac ketoprofen fenclofenac alcofenac orpanoxin zomopirac diflunisal pranoprofen zaltoprofen

The preferred compounds of formula (I) are those wherein "A" is selected from the ester or amide derivatives of naproxen, flurbiprofen or diclofenac. The most preferred

compounds are those wherein "A" is selected from the ester or amide derivatives of naproxen or flurbiprofen.

With respect to the other substituents of the compounds of formula (I), the preferred

compounds are those wherein:

X is O or NR;

R is H or C, alkyl;

Y is CH(OH), and m is 0 to 2 and n is 1 or 2, or Y is not present, and m is 1 or 2 and n

is 0 to 4; Z is a, b or d; R is H or C(O)CH₃; and

R" is CH₃. The most preferred compounds are those wherein: X is O or NR;

R is H;

Y is not present; m is 0 or 1 ;

n is 1; Z is a, or b; R' is H; C(O)CH₃; and

R" is CH₃.

The following compounds are particularly preferred:

2-(6-hydroxy-2,5J,8-tetramethyl-3,4-dihydro-2H-benzo[lJ-b]pyran-2-yl)methyl 2-(6- methoxy-2-naphthyl)propionate ("Compound A");

N-(2-(6-hydroxy-2,5J,8-tetramethyl-3,4-dihydro-2H-benzo[lJ-b]pyran-2-yl)methyl) 2-(6- methoxy-2-naphthyl)propionamide ("Compound B");

2-(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[lJ-b]pyran-2-yl)ethyl 2-(6- methoxy-2-naphthyl)propionate ("Compound C");

2-(5-hydroxy-2,4,6,7-tetramethyl-2J-dihydro-benzo[lJ-b]furan-2-yl)methyl 2-(6-methoxy- 2-naphthyl)propionate ("Compound D");

2-(5-hydroxy-2,4,6,7-tetramethyl-2J-dihydro-benzo[lJ-b]furan-2-yl)ethyl 2-(6-methoxy-2- naphthyl)propionate ("Compound E"); and

2-(6-hydroxy-2,5,7,8-tetramethyl-2J-dihydro-2H-benzo[lJ-b]pyran-2-yl)ethyl 2-(3-fluoro- 4-phenyl-phenyl)propionate ("Compound F").

(S)-6-methoxy-α-methyl-naphthaleneacetic acid, (R)-2-(6-acetoxy-3,4-dihydro-2,5,7,8- tetramethyl-2H-l- benzopyran-2-yl)ethyl ester ("Compound G"),

(R)N-(2-(6-acetoxy-2,5,7,8-tetramethyl-3,4-dihydro-2Η-benzo[l,2-b]pyran-2- yl)methyl) (S)(2-(6-methoxy-2-naphthyl)propionamide ("Compound H");

The most preferred bifunctional compound of the present invention is:

(S)-6-methoxy-α-methyl-naphthaleneacetic acid, (R)-2-(3,4-dihydro-6-hydroxy-2,5,7,8- tetramethyl-2H-l- benzopyran-2-yl)ethyl ester ("Compound X"), which is a particular stereoisomer of Compound C.

The compounds of formula (I) possess antinflammatory, antioxidant and antiproliferative activity. The compounds of formula (I) may be prepared by methods

disclosed in U.S. Patent No. 5,607,966 (Ηellberg et al.), the entire contents of which are

incorporated herein by reference.

Viscoelastic agents which may be included in the compositions of the present invention include, but are not limited to: sodium hyaluronate, chondroitin sulfate,

polyacrylamide, ΗPMC, proteoglycans, collagen, methylcellulose, carboxymethyl cellulose,

ethylcellulose, polyvinylpyrrolidone and keratan, all of various molecular weights and concentrations, or combinations thereof. Those skilled in the art will appreciate that the suitability of a given agent for a particular step in a surgical procedure will depend upon such things as the agent's concentration, average molecular weight, viscosity, pseudoplasticity, elasticity, rigidity, adherence (coatability), cohesiveness, molecular charge, and osmolality in solution. The agent's suitability will depend further on the function(s) which the agent is

expected to perform and the surgical technique being employed by the surgeon. The

concentration of the viscoelastic(s) in the compositions of the present invention will depend on various factors, as described below.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate or sodium

borate) may be added to the compositions to prevent pH drift under storage conditions.

One or more solubilizing agents may also be added to the compositions to solubilize a compound of formula (I). Typical solubilizing agents include polysorbate 20, 40, 60 and 80, Pluronic^® F-68, F-84 and P-103 (BASF Corp., Parsippany, NJ); cyclodextrin, tocopherol polyethyleneglycol succinate (TPGS), polyoxyl 35 castor oil (Cremephor EL^®), polyoxyl

hydrogenated castor oil (RH-40^®) and polyethylene glycol 660 hydroxysterate (SOLUTOL^® HS15) as well as other agents known in the art. Cremephor EL^®, RH-40^®, and SOLUTOL^® HS15 are available from BASF, Corp. The most preferred solubilizing agent is polyoxyl-35 castor oil. The amount of solubilizing agent included in the acidic compositions will vary,

depending on the particular viscoelastic composition and, in particular, the compound or

compounds of formula (I) contained in the composition. However, the amount of solubilizing agent to be added to the viscoelastic compositions will be an amount that solubilizes or

partially solubilizes the compounds of formula (I). In general, such an amount will be about

0.05 to 5.0% (w/v). Preferred amounts are about 0.5 to 2.0% (w/v). The most preferred

amount of polyoxyl 35-castor oil is 1.0% (w/v). However, it will be appreciated by those skilled in the art that these molecules may only be employed to the extent that they do not

detrimentally affect the viscoelastic properties of the compositions of the present invention.

The physiological antioxidants may be selected from antioxidants which are endogenously present in a mammal, provide for the stabilization of compounds of formula (I)

in a viscoelastic composition, do not cause substantial discoloration or precipitates to form in

the compositions, and which do not cause adverse side effects or interfere with the activity of formula (I) compounds in vivo. Examples of such antioxidants include, but are not limited

to, vitamin E, vitamin A, vitamin C (ascorbic acid or salts thereof), reduced glutathione, and derivatives thereof, or suitable combinations thereof. Other physiological antioxidants which possess a higher oxidative potential than the formula (I) compounds may be also be used as

stabilizers in the compositions, provided such antioxidants conform with the above criteria. The most preferred physiological antioxidant is ascorbic acid/ascorbate.

The amount of physiological antioxidant included in the viscoelastic compositions will vary depending on various factors such as the particular compound or compounds of

formula (I) to stabilize, the ingredients contained in the viscoelastic compositions and the efficacy of the antioxidant(s). However, such an amount will be that amount which stabilizes the compounds of formula (I) in the viscoelastic compositions. As used herein, a "stabilizing

amount" or "amount to stabilize" refers to that amount of one or more antioxidants which

prevents or limits the oxidation and/or breakdown of a compound of formula (I) in a

viscoelastic composition. Preferred antioxidant amounts will be about 0.005 to 0.5% (w/v) in

the viscoelastic compositions.

As stated above, ascorbic acid/ascorbate is the most preferred physiological

antioxidant. Ascorbate ions may be added to the viscoelastic composition in the form of

ascorbic acid and/or a soluble salt of ascorbate including, but not limited to, sodium ascorbate or calcium ascorbate. In general, the ascorbate ion concentration of the viscoelastic

composition will be about 0.5 to 5 millimoles/L ("mM") which generally corresponds to

about to 0.01 to 0J % (w/v). The preferred ascorbate source is sodium ascorbate. The preferred amount of ascorbate ion in the viscoelastic composition will be about 0.5 to 3J mM, which can be sourced by the addition of about 0.01 to 0.06 % (w/v) of sodium

ascorbate. The most preferred viscoelastic compositions of the present invention will contain

about 0.025 % (w/v) of sodium ascorbate.

Optionally, an amount of acetate ion (e.g., sodium acetate) of about 0.25-1.0% (w/v) may be combined with the antioxidants to aid in the stabilization of formula (I) compounds.

The addition of acetate to the viscoelastic compositions, however, may necessitate buffering

agent adjustments to compensate for the pH effects of the additional acetate ions on the compositions.

The viscoelastic compositions of the present invention may be used to treat patients afflicted with or prone to various types of cellular damage. In particular, these compositions

may be used to treat inflammation where prostaglandins, leukotrienes, inflammatory cytokines and chemokines, and other proinflammatory agents are known to participate,

including, but not limited to: 1) loss of vascular blood barrier function; 2) neutrophil accumulation; 3) tissue edema including conjunctiva swelling, conjunctiva congestion and

corneal haze; 4) cataract formation; 5) cellular proliferative disorders, including

neovascularizations, fibrosis and posterior capsule opacification; and 6) loss of membrane

The concentrations of the formula (I) compounds in the compositions will depend on

various factors, including the nature and severity of the condition to be treated. The

compositions of the present invention, however, will contain a therapeutically effective amount of one or more formula (I) compounds. As used herein, a "therapeutically effective amount" is that amount of a viscoelastic composition or compound(s) of formula (I) required

to prevent, reduce or ameliorate inflammation or other tissue or cellular damage and/or

trauma. Generally, the compositions may contain one or more of the compounds of the

present invention in a concentration of about 0J to about 250 micromoles/L ("μM").

Preferred compositions will have a formula (I) concentration of about 1.0 to about 100 μM

which will approximately correspond to about 0.00005 to 0.005 % (w/v).

As indicated above, compositions of the present invention may be used to treat ocular inflammation at the tissue or cellular level and represents a particularly important aspect of the invention. In particular, the compositions are useful in preventing, reducing or ameliorating post-surgical complications resulting from ocular surgery. Such complications

may include, but are not limited to, loss of vascular blood barrier function, tissue edema including conjunctiva swelling and congestion, corneal haze, cataract formation, retinal detachment, epiretinal proliferation, neovascular glaucoma, posterior capsule opacification,

vitreous hemorrhage, and cystoid macular edema neovascularizations. The frequency of these and other complications may be lessened by facilitating the prevention or amelioration of inflammation or other cellular or tissue discorders including cellular proliferative responses, by employing the improved viscoelastic compositions of the present invention

during surgery. Optionally, the patients may be treated pre- or post-surgery with other

compositions containing compounds of formula (I), to further alleviate such conditions.

The methods of the present invention involve the use of viscoelastic compositions

comprising various viscoelastic agents having different adherent or cohesive properties.

Those skilled in the art will recognize that the compositions of the present invention may be

employed by the skilled surgeon in a variety of surgical procedures. Given the advantages of each type of viscoelastic, the surgeon may employ various viscoelastic compositions of the present invention in a single surgical procedure. United

States Patent No. 5,273,056 (McLaughlin et al.) discloses methods which exploit the use of different viscoelastic compositions during a given ocular surgery, the entire contents of which

are incorporated herein by reference.

For portions of surgical procedures involving phacoemulsification and/or irrigation/aspiration, e.g., cataract surgery, it is generally preferable to use compositions

containing viscoelastic agents that possess relatively greater adherent properties and relatively

lesser cohesive properties. Such viscoelastic agents are referred to herein as "adherent" agents. The cohesiveness of a viscoelastic agent in solution is thought to be dependent, at least in part, on the average molecular weight of that agent. At a given concentration, the

greater the molecular weight, the greater the cohesiveness. The adherent agents, which are relatively lacking in cohesiveness, therefore will typically be of lower molecular weight; the molecular weight will typically be less than 1,000,000 daltons, preferably less than 750,000 daltons. To achieve a functionally desirable viscosity, the concentrations of the lower

molecular weight agents in the compositions will need to be relatively higher than for higher molecular weight agents. These concentrations will typically be at least about 2% w/v. For

example, compositions of the present invention may contain viscoelastic agents in similar to the VISCOAT® viscoelastic product which contains approximately 4% chondroitin sulfate

(25,000 daltons) and 3% sodium hyaluronate (700,000 daltons). Other compositions of the

present invention may be formulated in a similar fashion as Vitrax® which is believed to

contain approximately 3% sodium hyaluronate (500,000 daltons). For compositions

containing agents such as these, which are being employed primarily for protective purposes

as opposed to tissue manipulation purposes, a functionally desirable viscosity will be a viscosity sufficient to permit a protective layer of such agent to remain on the tissue or cells of concern during the surgical step(s) being performed. Such viscosity will typically be from

about 3,000 cps to about 60,000 cps (at shear rate of 2 sec"* and 25°C), and preferably will be

about 40,000 cps. Such adherent agents are capable of providing the protective function previously discussed, yet are not prone to inadvertent removal, which could jeopardize the

delicate tissue being protected.

Those portions of surgical procedures involving manipulation of delicate tissue are

generally better served by viscoelastic agents that possess relatively greater cohesive properties and relatively lesser adherent properties. Such agents are referred to herein as "cohesive" agents. Typically, these cohesive agents will possess average molecular weights in excess of 1,000,000 daltons and will have functionally desirable viscosity at concentrations

of not more than about 1.6% w/v. Examples of such cohesive agents are: the Provisc™ product, Healon®, Healon® GV, Amvisc® and Amvisc Plus®. For compositions containing cohesive agents such as these, which are being employed primarily for tissue manipulation or maintenance purposes as opposed to protective purposes, a functionally desirable viscosity will be a viscosity sufficient to permit the skilled surgeon to use such agent as a soft tool to

manipulate or support the tissue of concern during the surgical step(s) being performed. Such viscosity will depend upon the average molecular weight of the agent and its concentration in solution. Most preferred are cohesive agents having an average molecular weight of at least

about 2,000,000 daltons and a concentration in solution of between about 1.0 to about 1.4%

w/v. Such cohesive agents are capable of maintaining intraocular space and manipulating

tissue without adhering to it. When their purpose has been served, they can, because of their cohesive properties, be readily removed with minimal trauma to the surrounding tissue. The present invention may also be used in corneal transplant surgery. In conjunction

with the removal of the patient's corneal button, it is desirable to replace the aqueous humor with a highly viscous agent that will provide a firm bed to support the donor cornea, yet be

susceptible to easy removal upon completion of the surgery. The donor graft, on the other

hand, requires maximum protection from the surgical trauma and should therefore be coated with a different, more adherent agent. Corneal transplant surgery also involves the risks of inflammation and cellular damage. Thus, the compositions of present invention are also useful in this type surgery.

The compositions of the present invention may also be used in posterior segment

surgery. In a retinal detachment procedure, for example, compositions containing a highly viscous, cohesive agent such as sodium hyaluronate will typically be used to manipulate the

retina into position against the basement membrane of the choroid. Small amounts of a composition containing an adherent agent, such as the chondroitan sulfate may be injected behind the retina before or after such manipulation to temporarily maintain the contact between the retina and basement membrane while more permanent attachment procedures well known to those skilled in the art are performed (e.g., tacking or laser welding).

The compositions of the present invention may also be used to ameliorate

complications arising from glaucoma filtration surgery. Glaucoma filtration surgery involves the surgical creation of a fistula with a conjunctival flap. The fistualer which allows the direct drainage of aqueous humor from the anterior chamber into the conjunctival tissue,

thereby lowering the elevated intraocular pressure associated with glaucoma. However, in

many patients, the filtration "bleb" becomes scarred or healed over so that aqueous drainage can no longer occur. In order to maintain a deep chamber and enhance visualization during

the surgery, the viscoelastic compositions of the present invention will be injected into the anterior chamber of the eye. The addition of these compositions may ameliorate

inflammatory conditions resulting from such surgery, fibroplasia and may decrease bleb

failure.

Example 1

The following is an example of a preferred composition of the present invention:

Example 2

Example 3

The following is an example of a preferred composition of the present invention.

Example 4

The following are examples of a viscoelastic compositions of the present invention wherein "Compound" denotes a compound of formula (I):

Claims

What is claimed is:

1. A viscoelastic composition comprising an amount of one or more viscoelastic agent(s), an amount of one or more physiological antioxidant(s) and an amount of one or more compound(s) of the following formula (I):

A-X-(CH₂)_n-Y-(CH₂)_m-Z (I) wherein:

A is an non-steroidal anti-inflammatory agent (NSAIA) originally having a carboxylic acid;

A-X is an ester or amide linkage derived from the carboxylic acid moiety of the NSAIA, wherein X is O or NR;

R is H, C,-C₆ alkyl or C₃-C₆ cycloalkyl;

Y, if present, is O, NR, C(R)₂ , CH(OH) or S(O)_n. ; n is 2 to 4 and m is 1 to 4 when Y is O, NR, or S(O)_n. ; n is 0 to 4 and m is 0 to 4 when Y is C(R)₂ or is not present; n is 1 to 4 and m is 0 to 4 when Y is CH(OH); n' is 0 to 2; and

Z is:

wherein:

R is H, C(O)R, C(O)N(R)₂, PO₃ ^" , or SO₃ ^" ; and

R" is H or C,-C₆ alkyl; and pharmaceutically acceptable salts therefor.

2. The composition according to Claim 1 , wherein the viscoelastic agent(s) are selected from the group consisting of: sodium hyaluronate, chondroitin sulfate, polyacrylamide, HPMC, proteoglycans, collagen, methylcellulose, carboxymethyl cellulose, ethylcellulose, polyvinylpyrrolidone and keratan, all of various molecular weights and combinations thereof.

3. A composition according to Claim 1, wherein the physiological antioxidant(s) are selected from the group consisting of: vitamin E, vitamin A, vitamin C (ascorbic acid or salts thereof), reduced glutathione, and derivatives thereof, and suitable combinations thereof.

4. A composition according to Claim 3, wherein the physiological antioxidant is ascorbic acid/ascorbate.

5. The composition according to Claim 4, wherein the composition is comprised of cremophor El, hyaluronic acid sodium salt, dibasic sodium phosphate, monobasic sodium phosphate, sodium chloride, ascorbic acid, sodium ascorbate, a compound of formula (I), hydrochloric acid, sodium hydroxide and water.

6. A composition according to Claim 1, wherein the compound of formula (I) is selected from the group consisting of compounds wherein:

X is O or NR;

R is H or C, alkyl;

Y is CH(OH), and m is 0 to 2 and n is 1 or 2, or Y is not present, and m is 1 or 2 and n is 0 to 4;

Z is a, b or d;

R' is H or C(O)CH₃; and

R" is CH₃.

7. A composition according to Claim 1 , wherein the compound of formula (I) is selected from the group consisting of compounds wherein the non-steroidal anti- inflammatory agent is selected from the group consisting of: fenamic acids; indoles; and phenylalkanoic acids.

8. A composition according to Claim 1, wherein the compound of formula (I) is selected from the group consisting of compounds wherein the non-steroidal anti- inflammatory agent is selected from the group consisting of: loxoprofen; tolfenamic acid; indoprofen; pirprofen; clidanac; fenoprofen; naproxen; fenclorac; meclofenamate; benoxaprofen; carprofen; isofezolac; aceloferac; fenbufen; etodolic acid; fleclozic acid; amfenac; efenamic acid; bromfenac; ketoprofen; fenclofenac; alcofenac; orpanoxin; zomopirac; diflunisal; flufenamic acid; niflumic acid; mefenamic acid; pranoprofen; zaltoprofen; indomethacin; sulindac; tolmetin; suprofen; ketorolac; flurbiprofen; ibuprofen; and diclofenac.

9. A composition according to Claim 8, wherein the compound of formula (I) is selected from the group consisting of compounds wherein:

X is O or NR;

R is H or C, alkyl;

Z is a, b or d;

R' is H or C(O)CH₃; and

R" is CH₃.

10. A composition according to Claim 9, wherein the compound of formula (I) is selected from the group consisting of compounds wherein the non-steroidal anti- inflammatory agent is selected from the group consisting of naproxen, flurbiprofen and diclofenac.

11. A composition according to Claim 1, wherein the compound of formula (I) is selected from the group consisting of:

or stereoisomers thereof.

12. A composition according to Claim 1, wherein the composition is comprised of: 1% w/v hyaluronic acid, sodium salt; 0.056% w/v dibasic sodium phosphate (anhydrous); 0.004% w/v monobasic sodium phosphate (monohydrate); 0.84% w/v sodium chloride; 0.00146% of a compound of formula (II):

0.05% (w/v) polyoxyl-35 castor oil; and water.

13. A method of treating mammalian tissues which comprises administering a viscoelastic composition to a mammal, the viscoelastic composition comprising one or more viscoelastic agent(s), one or more physiological antioxidant(s) and one or more compound(s) of the following formula (I):

A-X-(CH₂)_n-Y-(CH₂)_m-Z (I) wherein:

R is H, C,-C₆ alkyl or C₃-C₆ cycloalkyl;

Y, if present, is O, NR, C(R)₂ , CH(OH) or S(O)„. ; n is 2 to 4 and m is 1 to 4 when Y is O, NR, or S(O)_n. ; n is 0 to 4 and m is 0 to 4 when Y is C(R)₂ or is not present; n is 1 to 4 and m is 0 to 4 when Y is CH(OH); n' is 0 to 2; and

Z is:

wherein:

R' is H, C(O)R, C(O)N(R)₂, PO₃ ^", or SO₃J and

R" is H or C,-C₆ alkyl; and pharmaceutically acceptable salts therefor.

14. The method according to Claim 13, wherein the viscoelastic agent(s) are selected from the group consisting of: sodium hyaluronate, chondroitin sulfate, polyacrylamide, HPMC, proteoglycans, collagen, methylcellulose, carboxymethyl cellulose, ethylcellulose, polyvinylpyrrolidone and keratan, all of various molecular weights and combinations thereof.

15. A method according to Claim 13, wherein the physiological antioxidant(s) are selected from the group consisting of: vitamin E, vitamin A, vitamin C (ascorbic acid or salts thereof), reduced glutathione, and derivatives thereof, and suitable combinations thereof.

16. A method according to Claim 15, wherein the physiological antioxidant is ascorbic acid/ascorbate.

17. The method according to Claim 13, wherein the composition is comprised of cremophor El, hyaluronic acid sodium salt, dibasic sodium phosphate, monobasic sodium phosphate, sodium chloride, ascorbic acid, sodium ascorbate, a compound of formula (I), hydrochloric acid, sodium hydroxide and water.

18. A method according to Claim 13, wherein the compound of formula (I) is selected from the group consisting of compounds wherein:

X is O or NR; R is H or C, alkyl;

Z is a, b or d;

R is H or C(O)CH₃; and

R" is CH₃.

19. A method according to Claim 13, wherein the compound of formula (I) is selected from the group consisting of compounds wherein the non-steroidal anti- inflammatory agent is selected from the group consisting of: fenamic acids; indoles; and phenylalkanoic acids.

20. A method according to Claim 13, wherein the compound of formula (I) is selected from the group consisting of compounds wherein the non-steroidal anti- inflammatory agent is selected from the group consisting of: loxoprofen; tolfenamic acid; indoprofen; pirprofen; clidanac; fenoprofen; naproxen; fenclorac; meclofenamate; benoxaprofen; carprofen; isofezolac; aceloferac; fenbufen; etodolic acid; fleclozic acid; amfenac; efenamic acid; bromfenac; ketoprofen; fenclofenac; alcofenac; orpanoxin; zomopirac; diflunisal; flufenamic acid; niflumic acid; mefenamic acid; pranoprofen; zaltoprofen; indomethacin; sulindac; tolmetin; suprofen; ketorolac; flurbiprofen; ibuprofen; and diclofenac.

21. A method according to Claim 20, wherein the compound of formula (I) is selected from the group consisting of compounds wherein:

X is O or NR; R is H or C, alkyl;

Z is a, b or d; R' is H or C(O)CH₃; and R" is CH,.

22. A method according to Claim 21, wherein the compound of formula (I) is selected from the group consisting of compounds wherein the non-steroidal anti- inflammatory agent is selected from the group consisting of naproxen, flurbiprofen and diclofenac.

23. A method according to Claim 13, wherein the compound of formula (I) is selected from the group consisting of:

or stereoisomers thereof.

24. A method according to Claim 13, wherein the composition is comprised of: 1% w/v hyaluronic acid, sodium salt; 0.056% w/v dibasic sodium phosphate (anhydrous); 0.004% w/v monobasic sodium phosphate (monohydrate); 0.84% w/v sodium chloride; 0.00146% of a compound of formula (II):

0.05% (w/v) polyoxyl-35 castor oil; and water.

25. A method according to Claim 13, wherein the viscoelastic composition is administered during ocular surgery.