TEAR SUBSTITUTE

FIELD OF THE INVENTION

The present invention concerns a tear substitute, usually also called eye drops, for the treatment of ocular surface disease like dry eye disease, a fluid to be used as a tear substitute, as well as a method for producing a tear substitute.

BACKGROUND OF THE INVENTION

Tear substitutes play an essential role in the treatment of ocular surface disease. As a lubricant they are intended to minimize the friction between lid and corneal epithelium during blinking. Their water binding capacity contributes to the

hydration of irritated eyes.

For the physiological function of natural human tears it is characteristic that they exhibit high viscosity in the absence of shear stress as typically 65 mPa-s in ^' the open eye, and low viscosity during blinking as typically 10 mPa-s. This ensures high stability of the tear film in the open eye and low shear stress on the corneal epithelium during blinking. However, the flow characteristics of most of the currently available tear substitutes does not mimic the rheology of human tears. Most eye drops exhibit an almost Newtonian flow characteristics, i.e. they have either low or high viscosity both in the open eye and during blinking . Over the last 15 years numerous hyaluronan eye drops have become available, claiming viscoelastic flow characteristics and long persistence in the eye. Measurements of the flow characteristics of more than 40 different hyaluronan (HA) eye drop brands resulted in that those containing low HA concentration act like Newtonian fluids with low viscosity whereas those with high HA concentration (gels) have high viscosity during blinking causing blurring and excess shear stress on the corneal epithelium, and nevertheless have lower viscosity than natural tears in healthy eyes between blinking.

Only the use of very high molecular weight HA (« 3 MDa) in approximately 0.15 percent concentration can mimic the flow characteristics of human tears. The relation between molecular weight and intrinsic viscosity [η] in m ³ /kg is given through the Mark-Houwink equation

[η] = k · (M _rra ) ^a with M _rm being the molecular mass in MDa

and the coefficients

k = 1.3327 · 10 ^"4

and

a = 0.6691

which values for k and a having been found as most

predictive .

Another important aspect is the biochemical function of HA. HA is the most important component of the extracellular matrix of multilayer epithelia without blood supply, like the corneal epithelium. HA organizes the extracellular matrix, provides water storage and retention, is responsible for the diffusion of nutrients and metabolic products, controls keratinocyte proliferation and differentiation, is an efficient radical scavenger in cases of UV exposure, infection, oxidative stress and inflammatory processes with tissue necrosis, and facilitates the migration of epithelial cells during wound healing. The molecular weight of HA in the extracellular matrix of healthy epithelia is about 3 to 4 MDa . In case of increased HA

degradation, e.g. due to inflammatory processes, HA exhibits a molecular weight dependent signal function. While high molecular weight HA acts anti-angiogenetically and immunosuppressively, small to medium size HA molecules induce inflammatory factors and stimulate immunity and angiogenesis . The binding of free HA to cell membrane receptors protects the cells from lymphocytic and macrophagic attack.

The half-life of HA in the epithelial extracellular matrix is only about 24 hours. Due to intrinsic aging, commencing from the fifth decade of life the amount of freely available and

extractible HA in the intercellular spaces decreases rapidly. This is the main reason for the loss of hydration and thickness of the epidermis in older people, suggesting that HA may also play an essential role in age-related dry eye.

US 2004/0013729 Al discloses to use methylcellulose for

increasing the time available for agents to contact the cornea. Although such methylcellulose in US 2004/0013729 Al is named a viscoelastic polymer, this is against the true meaning of

viscoelasticity because methylcellulose does not have

viscoelastic behavior but largely acts like a Newtonian fluid.

SUMMARY OF THE INVENTION The objective of the invention is to provide for tear substitute for improved treatment of ocular surface disease like dry eye disease . This objective is reached with tear substitute according to claim 1. Further advantageous and preferred embodiments are given in the dependent claims and through combinations thereof.

According to the present invention, a tear substitute comprises hyaluronan is characterized by a viscoelastic flow

characteristics with the zero shear viscosity being > 50 mPa -s, and the shear viscosity at 1000 s ^_1 being < 12 mPa-s.

Also according to the present invention, a tear substitute comprises hyaluronan with a hyaluronan intrinsic viscosity

[η] > 2.5 m ³ /kg and a concentration of < 0.2 % w/v.

It is also contemplated by the present invention that the tear substitute has the hyaluronan intrinsic viscosity [η] > 2.9 m ³ /kg.

According to the invention, the tear substitute may further comprise only substances naturally present in the human eye plus eventually substances which are pharmacologically, metabolically, immunologically and/or anti-microbial effective, or being

preservative-free.

Instead, the tear substitute may further comprise

glycosaminoglycanes , electrolytes, and buffers. The tear

substitute may further provide that the glycosaminoglycanes comprise hyaluronan, and/or the electrolytes comprise sodium chloride, and/or the buffers comprise a phosphate buffer in concentration < 1.45 mmol/1 or trometamol. As a further alterative of the invention, the tear substitute may comprises < 2 % w/v of substances which are pharmacologically, metabolically, immunologically and/or anti-microbial effective. A further embodiment of the invention provides that the tear substitute comprises < 0.1 % w/v of substances which are

pharmacologically, metabolically, immunologically and/or antimicrobial effective. An even further embodiment of the invention provides that the tear substitute comprises < 0.01 % w/v

substances which are pharmacologically, metabolically,

immunologically and/or anti-microbial effective.

Further according to the invention, a fluid comprises hyaluronan and having a viscoelastic flow characteristics with the zero shear viscosity being > 50 mPa-s, and the shear viscosity at 1000 s ^-1 being < 12 mPa -s, characterized in that said fluid being used as a tear substitute.

Also according to the invention, a fluid comprises hyaluronan with an intrinsic hyaluronan viscosity [η] > 2.5 m ³ /kg and a concentration of < 0.2 % w/v, characterized in that said fluid being used as a tear substitute.

It is also contemplated by the present invention that the fluid has the the hyaluronan intrinsic viscosity [η] > 2.9 m ³ /kg.

According to the invention, the fluid may further comprise only substances naturally present in a human eye; and substances which are pharmacologically, metabolically, immunologically and/or anti-microbial effective, or being preservative-free. Alternatively, the fluid may further comprise

glycosaminoglycanes, electrolytes, and buffers. Such a fluid may further provide that the glycosaminoglycanes comprise hyaluronan, and/or the electrolytes comprise sodium chloride, and/or the buffers comprise a phosphate buffer in concentration

< 1.45 mmol/1 or trometamol.

In a further alternative of the invention, the fluid may comprise

< 2 % w/v substances which are pharmacologically, metabolically, immunologically and/or anti-microbial effective. A further embodiment of the invention provides that the fluid comprises

< 0.1 % w/v substances which are pharmacologically,

metabolically, immunologically and/or anti-microbial effective. A further embodiment of the invention provides that the fluid comprises < 0.01 % w/v substances which are pharmacologically, metabolically, immunologically and/or anti-microbial effective.

[0021]

According to the invention, a method of producing a tear

substitute comprises a step of using viscosity-increasing

substances for reaching a viscoelastic flow characteristics with the zero shear viscosity being > 50 mPa -s, and the shear

viscosity at 1000 s ^_1 being < 12 mPa-s. A method of producing a tear substitute may comprise a step of using hyaluronan with a hyaluronan intrinsic viscosity [η] > 2.5 m ³ /kg and a concentration of < 0.2 % w/v. The method may further provide that the hyaluronan intrinsic viscosity [η] > 2.9 m ³ /kg. According to the method, the viscosity-increasing substances are preferably added towards or during or as a final step. It is further preferred that a step of mixing is carried out so as to reach or until reaching a homogeneous mixture. The method may also contemplate a step of providing as a basis initially

purified water or water for injection. The method may further contemplate first adding electrolytes, buffers and substances which are not increasing the viscosity to the purified water or water for injection.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In the following the invention is explained by way of examples only.

According to a first aspect of the invention there is provided tear substitute containing hyaluronan and having a viscoelastic flow characteristics with the zero shear viscosity being

> 50 mPa-s, and the shear viscosity at 1000 s ^-1 being < 12 mPa-s.

Viscoelasticity is defined as characteristics of a fluid having both viscous and elastic properties. The zero shear viscosity is determined as the steady shear plateau viscosity at vanishing shear rate. For highly viscous formulations, measurement with a controlled stress rheometer is preferred which is well known to a man skilled in the art. The aforementioned first aspect also is fulfilled by a fluid, which contains hyaluronan and has a viscoelastic flow

characteristics with the zero shear viscosity being > 50 mPa -s, and the shear viscosity at 1000 s ^_1 being < 12 mPa -s, wherein said fluid being used as tear substitute.

Both the tear substitute and the fluid of the first aspect preferably being at least essentially mucin-free or in other words having a mucin concentration of < 0.3 % w/v. This means that the flow behaviour or properties essentially is reached or adjusted by hyaluronan and not by mucin naturally present in the tear fluid and mainly responsible for the flow behavior thereof.

Furthermore, within the scope of said first aspect of the present invention there also is a method of producing a tear substitute, comprising the use of substances for reaching a viscoelastic flow characteristics with the zero shear viscosity being > 50 mPa -s, and the shear viscosity at 1000 s ^"1 being < 12 mPa-s. Mucin concentration if any is less than 0.3 % w/v.

Next, according to a second aspect of the invention there is provided a tear substitute containing hyaluronan with an

intrinsic viscosity [η] > 2.5 m ³ /kg and a concentration of

< 0.2 % w/v. Preferably the hyaluronan intrinsic viscosity [η] > 2.9 m ³ /kg.

The aforementioned second aspect also is fulfilled by a fluid, containing hyaluronan with an intrinsic viscosity [η] > 2.5 m ³ /kg and a concentration of < 0.2 % w/v, wherein said fluid being used as a tear substitute. Preferably the hyaluronan intrinsic

viscosity [η] > 2.9 m ³ /kg. Both the tear substitute and the fluid of the second aspect preferably being at least essentially mucin-free or in other words having a mucin concentration of < 0,3 % w/v. This means that the flow behaviour or properties essentially . is reached or adjusted by hyaluronan and not by mucin naturally present in the tear fluid and mainly responsible for the flow behavior thereof. Also, within the scope of said second aspect of the present invention there is a method of producing a tear substitute, comprising the use of hyaluronan with an intrinsic viscosity [η] > 2.5 m ³ /kg and a concentration of < 0.2 % w/v. Mucin

concentration if any is less than 0.3 % w/v. Preferably the hyaluronan intrinsic viscosity [η] > 2.9 m ³ /kg.

Preferably there are contained or used only substances which are naturally present in the human eye plus eventually substances which are pharmacologically, metabolically, immunologically and/or anti-microbial effective.

It is furthermore preferred that are contained or used

glycosaminoglycanes , electrolytes, and buffers. Especially the glycosaminoglycanes include hyaluronan, and/or the electrolytes include sodium chloride, and/or the buffers include a phosphate buffer in concentration < 1.45 mmol/1 or trometamol.

An even further preferred embodiment is the content or use of < 2 % w/v, especially < 0.1 % w/v, and especially preferred < 0.01 % w/v substances which are pharmacologically,

metabolically, immunologically and/or anti-microbial effective.

With regard to the method within the scope of the present invention it is further preferred, that substances which are increasing the viscosity are added towards or during or as a final step.

According to another preferred embodiment of the method of the present invention, mixing is carried out so as to reach or until reaching a homogeneous mixture. As an alternative or in addition it is preferred to initially provide for purified water or water for injection as a basis, and then, especially, electrolytes, buffers and substances which are not increasing the viscosity are added at first to the purified water or water for injection. For comparison with tear substitutes or eye drops having other specifications tests of the tear substitute having the following specifications were made with patients with ocular surface disease and achieved excellent and the best results:

The invention is described only exemplarily by the embodiments in the description and drawings and is not limited thereto but rather includes all variations, modifications, substitutions, and combinations the expert may take from the complete documents of this application under consideration of and/or combination with his specific knowledge.