Ophthalmic composition

Ophthalmic composition for use in ocular surgery includes an aqueous solution of sodium hyaluronate with a concentration within the range of 18-40 mg sodium hyaluronate/ml solution and the molecular mass of sodium hyaluronate being in the range of 1.times.10.sup.6 -10.times.10.sup.6 <M>.sub.r,M. In a method for conducting ocular surgery, the composition is introduced into the eye as a surgical aid. The composition may be used in a method for conducting cataract surgery.

OPHTHALMIC COMPOSITION 
The present invention relates to an ophthalmic composition for use in 
ocular surgery and a method for conducting ocular surgery. In particular 
the invention relates to a composition of sodium hyaluronate with a 
specifically defined molecular mass and concentration, for use in ocular 
surgery. 
Intraocular lens implantation has today become routine surgery. A major 
tool to accomplish this was the introduction of Healon.RTM. (1980), the 
high molecular mass, viscoelastic, noninflammatory preparation of sodium 
hyaluronate. Since then, the cataract surgery has undergone a tremendous 
progress and many viscoelastic products have been developed. Typically 
these products are aqueous solutions containing a polysaccharide such as 
sodium hyaluronate, sodium chondroitin sulfate and 
hydroxypropylmethylcellulose, at concentrations varying from 10-70 mg/ml. 
The molecular mass (expressed as mass average relative molecular 
mass,&lt;M&gt;.sub.r,M) varies from about 20,000 (chondroitin sulfate) to about 
5,000,000 (sodium hyaluronate). 
A cataract surgery of today can be divided into several steps. The first 
step is pupil dilatation and local anaesthesia. The operation starts by 
making an incision into the anterior chamber of the eye. When the eye is 
punctured, the aqueous humour leaks out and the anterior chamber becomes 
shallow. A viscoelastic product is injected into the anterior chamber, 
which then regains its former shape and depth. The viscoelastic product 
maintains the anterior chamber and protects the vulnerable tissues, 
especially the endothelial cells on the cornea. 
The next step is to make a hole in the anterior lens capsule, a 
capsulotomy, which can be done in several ways. The viscoelastic product 
helps the surgeon by creating enough space by maintaining the anterior 
chamber depth and stabilize the lens. 
Extraction of the lens nucleus can be done in different ways, e.g. planned 
ECCE (extracapsular cataract extraction) or phacoemulsification (phaco) 
using ultrasound. The remaining lens cortex is removed by 
irrigation/aspiration. 
After removal of the lens, viscoelastic product is again injected to 
inflate the capsular bag and to deepen the anterior chamber to make space 
for the intraocular lens implantation. The viscoelastic product maintains 
the space in the anterior chamber and is a very important protector of the 
endothelial cells and of other intraocular tissues from direct contact 
with the lens. 
Upon completion of surgery, the viscoelastic product is removed from the 
eye by irrigation/aspiration and substituted by physiological salt 
solution. If needed the wound is sutured. 
Planned ECCE is the term normally used when the lens nucleus is removed in 
one piece. Planned ECCE requires an incision size of 9-12 mm. 
In the method by phaco the lens nucleus is disintegrated with the help of 
ultrasound and is aspirated through a small incision, usually 
approximately 3 mm. An intraocular lens, foldable or not foldable, is then 
implanted through the incision. Phaco is the most modern method, which has 
increased rapidly in popularity due to the improved patient outcome. The 
small incision needed, reduces the amount of astigmatism induced by the 
surgery. Phaco is the most commonly employed technique in most countries 
and it will be the dominating technique for the foreseeable future. 
The demands on the viscoelastic products used in the surgical steps 
mentioned above are different. Current viscoelastic products can be 
divided into two broad groups. The first is a group of highly viscous 
cohesive products containing high molecular mass polysaccharides that 
already at moderate concentrations (about 1 mg/ml) form a flexible 
entangled molecular network and which have a high zero-shear viscosity. 
The second group consists of lower zero-shear viscosity dispersive 
products containing low molecular mass polysaccharides in high (about 70 
mg/ml) concentrations, which tend to disperse in the eye and which do not 
exhibit cohesive properties even at high concentrations. 
The dispersive products typically contain high concentration 
(approximately. 70 mg/ml) of low molecular mass polysaccharides (average 
mass average relative molecular mass about 200,000). These products 
fracture easily and stay in the anterior chamber during the turbulent 
phacoemulsification procedure. However, these products have poor space 
maintaining properties. Furthermore, these products can not easily be 
removed from the anterior chamber at the close of surgery, and frequently 
require high pressure to expel from the syringe through an ophthalmic 
cannula into the anterior chamber. 
The cohesive products contain high molecular mass polysaccharide (mass 
average relative molecular mass: 1 to 5 million) at low concentration 
(10-15 mg/ml). The latter products can easily be injected through thin 
cannulas, and exhibit good space-maintaining properties. They can also 
easily be extracted from the anterior chamber due to the cohesive 
properties. However, as a consequence of the cohesive properties, these 
products frequently leave the chamber as a chunk during the turbulent 
phacoemulsification procedure. 
The cohesive viscoelastic products are used to displace and stabilize 
tissues and to pressurize the anterior chamber. However, there is a risk 
that they leave the eye too quickly during phaco and leave the endothelium 
not well protected. On the contrary, the dispersive viscoelastic products 
stay in the anterior chamber during phaco but do not stabilize tissues 
very well. So far none of the viscoelastic products available have been 
able to match all viscoelastic needs during cataract surgery with 
phacoemulsification and it has been assumed impossible to make such a 
product. 
To achieve the optimal viscoelastic effect in all the surgical steps, U.S. 
Pat. No. 5,273,056 suggests use of different viscoelastic products in the 
various steps. U.S. Pat. No. 5,273,056 uses a combination of both cohesive 
and dispersive viscoelastic products. A similar solution has been 
suggested by Dr. Steve A. Arshinoff in the description of the "soft-shell" 
technique (Ocular Surgery News, International edition, vol. 14 no. 18 
1996, p. 17, "Soft-shell" technique uses two types of viscoelastic 
products" reported by Harvey Black) 
The object of the present invention is to obtain an improved ophthalmic 
composition for use in ocular surgery. Further, the object with the 
present invention is to present a viscoelastic product that could be used 
in all steps of cataract surgery, especially cataract surgery with 
phacoemulsification. The object of the present invention is to obtain a 
viscoelastic product which combines dispersive and cohesive qualities. 
Yet a further object of the invention is an improved method of ocular 
surgery. 
The objects of the invention are achieved by the composition and the method 
as described herein. 
According to the present invention an ophthalmic composition for use in 
ocular surgery is obtained. The composition comprises an aqueous solution 
of sodium hyaluronate with a concentration within the range of 18-40 mg 
sodium hyaluronate/ml solution and the molecular mass of sodium 
hyaluronate being in the range of 1.times.10.sup.6 -10.times.10.sup.6 
&lt;M&gt;.sub.r,M. 
According to a further aspect of the invention use of an aqueous solution 
of sodium hyaluronate with a concentration within the range of 18-40 mg 
sodium hyaluronate/ml solution and the molecular mass of sodium 
hyaluronate being in the range of 1.times.10.sup.6 -10.times.10.sup.6 
&lt;M&gt;.sub.r,M, for the manufacture of a composition for ocular surgery is 
obtained. 
According to yet a further aspect of the invention a method for conducting 
ocular surgery is obtained. According to the method a composition 
comprising an aqueous solution of sodium hyaluronate with a concentration 
within the range of 18-40 mg sodium hyaluronate/ml solution and the 
molecular mass of sodium hyaluronate being in the range of 
1.times.10.sup.6 -10.times.10.sup.6 &lt;M&gt;.sub.r,M is introduced into the eye 
as a surgical aid. 
According to yet a further aspect of the invention a method for conducting 
cataract surgery in an eye having an anterior chamber, a posterior chamber 
and a lens capsule is obtained. The method comprises the following steps: 
a) entering the anterior chamber by making an incision and injecting a 
composition comprising an aqueous solution of sodium hyaluronate with a 
molecular mass within the range of 1.times.10.sup.6 -10.times.10.sup.6 
&lt;M&gt;.sub.r,M and a concentration within the range of 18-40 mg/ml into the 
anterior chamber; 
b) performing a capsulotomy; 
c) removing of lens and lens cortex; 
d) injecting into the lens capsule the composition used in step a) and 
implanting an intraocular lens; 
e) optionally, removing the composition injected in steps a) and d). 
With the present invention it was surprisingly found that the composition 
according to the invention, with the increased concentration of the high 
molecular mass sodium hyaluronate, had an excellent performance in all 
steps of ocular surgery. The new hyaluronate composition is both cohesive 
and dispersive and stays in the anterior chamber during phaco 
emulsification. Because of these specific qualities the composition has a 
very good protecting effect against, as well mechanical damage, as against 
the free radicals which are formed by the ultrasound during the 
phacoemulsification procedure. The composition is also cohesive enough to 
maintain the anterior depth. The fact that the composition works well 
during the phacoemulsification step is surprising considering this 
composition is more cohesive than known sodium hyaluronate products on the 
market. A possible explanation to the obtained result is that by making 
the solution more cohesive, apparently a state is reached where the 
solution also becomes brittle. In highly turbulent flow (as during phaco), 
the solution close to the phaco instrument fractures, while a substantial 
amount of solution remains in the anterior chamber as a soft shell. The 
ophthalmic composition according to the invention has preferably a 
concentration within the range of 18-35 mg/ml, most preferably within 
20-28 mg/ml and the molecular mass of the sodium hyaluronate is preferably 
within the range 1.times.10.sup.6 -6.times.10.sup.6 &lt;M&gt;.sub.r,M, most 
preferably within 2.5.times.10.sup.6 -5.times.10.sup.6 &lt;M&gt;.sub.r,M,. 
The ophthalmic composition according to the invention can be used in all 
types of ocular surgery, such as cataract surgery, glaucoma surgery, 
vitreous surgery and posterior segment surgery. The cohesive qualities of 
the present composition are very suitable in glaucoma, vitreous and 
posterior segment surgery both as a protector of eye tissue and to move 
and hold tissue away from the operation area and as an antiadherence 
product. However, the composition is especially suitable for cataract 
surgery with phacoemulsification. Thus, in a preferred embodiment of the 
present invention step c) in the above mentioned method is made by 
phacoemulsification. At the end of the surgery the composition according 
to the invention is preferably removed from the eye, but can be left in 
special cases. 
The composition according to the invention is prepared in a conventional 
manner by dissolving the sodium hyaluronate in an aqueous solvent 
containing physiological amounts of sodium chloride to the required 
concentration of sodium hyaluronate. Sodium hyaluronate of suitable 
molecular mass is today a commercially available product. The solvent may 
also contain other inorganic salts such as calcium-, magnesium-and 
potassium chloride in physiological concentrations. Suitably the solvent 
may also contain buffering agents such as phosphate, acetate, carbonate or 
citrate in physiological concentrations. The solvent may also contain 
other physiological compounds. As mentioned above the composition has a 
good protecting effect against the free radicals produced during phaco. In 
order to increase this protective effect a compound acting as a scavenger 
can be added to the composition. As suitable scavengers can be mentioned 
superoxidedismutase (SOD), mannitol, glutathione or other known scavenger 
compounds acceptable to the eye.