WO2003097007A2

WO2003097007A2 - Aqueous ophthalmic composition comprising a lyotropic mesomorphic lipid

Info

Publication number: WO2003097007A2
Application number: PCT/EP2003/004708
Authority: WO
Inventors: Giovanni Cavallo; Alberto Campana; Patrizia Dragone; Francesca Mancini
Original assignee: Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A.
Priority date: 2002-05-15
Filing date: 2003-05-01
Publication date: 2003-11-27
Also published as: ITMI20021033A0; WO2003097007A3; ITMI20021033A1; AU2003232721A1

Abstract

A substantially transparent aqueous ophthalmic composition comprising a lyotropic mesomorphic lipid and a pegylated derivative of a lyotropic mesomorphic lipid. It is further disclosed a sterile aqueous ophthalmic composition obtained by - adding a lyotropic mesomorphic lipid and a pegylated derivative of a lyotropic mesomorphic lipid to water, and - sterilizing the thus obtained aqueous composition via heating.

Description

"Aqueous ophthalmic composition comprising a lyotropic mesomorphic lipid"

* * * * ** *

The present invention relates to an aqueous ophthalmic composition comprising a lyotropic mesomorphic lipid.

More particularly, the present invention relates to an aqueous ophthalmic composition comprising a lyotropic mesomorphic lipid and a pegylated derivative of a lyotropic mesomorphic lipid.

In normal conditions, the natural Iacrimal fluid is able to keep the corneal surface constantly moist and lubricated with very small volumes. This result is achieved owing to very complex characteristics of the natural Iacrimal fluid as regards its structure, its chemical composition, and its physical properties (Holly F.J., Lemp M.A., Tear physiology and dry eyes. Surv. Ophthalm. 22: 69-87, 1977). In particular, with regard to the structural characteristics, the natural

Iacrimal film has a thickness of about 7 μm and is constituted essentially of two layers:

- a lipid layer of approx. 0.1 μm in its external part, and

- an aqueous layer in the internal part in contact with the cornea. A lack of Iacrimal fluid causes a sensation of irritation and annoyance

(dry eye syndrome).

To date, numerous compositions have been proposed, which are commonly called "artificial tears", with the aim of alleviating dry eye syndrome. Artificial tears have been proposed, for example, for alleviating the symptoms of keratoconjunctivitis sicca, exposure keratopathies and other situations that can be attributed to dry eye syndrome. In addition, they have been proposed for alleviating problems for wearers of contact lenses, especially in the case of hard lenses. However, as far as the inventors are aware, none of the artificial tears proposed to date has the property of the natural Iacrimal fluid of forming two layers, one aqueous in the internal part in contact with the cornea and an external lipid layer. The person skilled in the art will appreciate that an ophthalmic composition capable of mimicking the behaviour of the natural Iacrimal fluid would also be very useful as a base for medicated ophthalmic compositions, especially for those active principles for which it is possible to reach the desired concentration in the aqueous phase in contact with the cornea.

Now it has been found, surprisingly, that such properties are possessed by an aqueous composition comprising a lyotropic mesomorphic lipid and a pegylated lipid.

Some ophthalmic compositions comprising lipids are known. However, they have not been proposed as artificial tears and do not possess the above mentioned properties which are required to be capable of mimicking the behaviour of the natural Iacrimal fluid.

WO 96/31196 discloses compositions comprising, in an aqueous carrier, a lipid and a material which is capable of stabilizing the composition. The stabilizing material is associated non-covalently with said lipid and is present in an amount sufficient to coat the lipid but insufficient to raise the viscosity of the composition. The compositions are particularly suitable for use in diagnostic applications, including ultrasound. However, they are said to be also suitable for intraocular administration.

The compositions can take the form of vesicular compositions, such as micelles and liposomes that, thanks to the association with the stabilizing lipid, have a very large size ranging from about 25 to about 42 μm (25,000 - 42,000 nm) as shown in Table II. WO 97/21429 discloses ether-linked phospholipids derivatized with polyethylene glycol at the polar head group. Lipid bilayers containing these phospholipids show high oxidative stability. Also disclosed is the use of PEG-derivatized ether-linked lipids in moisturizing and radiation- protective cosmetic compositions, including eye drops. The composition may take the form of small unicelamellar vesicles (SUV's) having a size in the range of 40 - 80 nm (page 9, line 26 to 29).

WO 01/01960 discloses pharmaceutical compositions and methods for improved solubilization of triglycerides and improved delivery of therapeutic agents. The compositions include a triglyceride and a carrier, where the carrier is formed from a combination of at least two surfactants, at least one of which is hydrophilic. Upon dilution with an aqueous solvent, the composition forms an aqueous dispersion of the triglyceride and surfactants having an absorbance (400 nm) level of less than about 0.3 and often less than about 0.1 at 100X dilution. The minimum absorbance level at 400 nm of the 100X (w/v) dilution in deionized water is of 0.017 (Example 31).

In the present description and in the appended claims, the term "mesomorphic" is used as a synonym of liquid crystal and the expression "liquid crystal" shall mean a thermodynamically stable phase characterized by anisotropy of properties without the presence of a crystal lattice, which generally exists in the temperature range between the solid phase and the isotropic liquid phase, hence the term mesophase. The term "lyotropic" shall mean a material in which the property of

"liquid crystal" appears to be due to the presence of a diluent, with mesophases depending on the concentration of the diluent and on the temperature. The expression "lyotropic mesomorphic lipid" shall mean a polar lipid that is insoluble in water but which forms liquid crystals in the presence of water. Preferably, [it is] in the form of a stable monolayer.

Accordingly, in a first aspect the present invention relates to an aqueous ophthalmic composition characterized in that it comprises a lyotropic mesomorphic lipid and a pegylated derivative of a lyotropic mesomorphic lipid and in that it is substantially transparent.

In the present description and in the appended claims, the expression "substantially transparent" is used to mean a composition which has at least one of the following features:

- is substantially free of particles having an average size larger than 30 nm,

- has an absorbance (measured at 400 nm) of less than 0,05 when it is not diluted and less than 0,001 at 100X (w/v) dilution in deionized water.

Preferably, the composition of the present invention is substantially free of particles having an average size larger than 20 nm.

Typically, the composition of the present invention gives a signal < 20 kHz when it is tested by the light scattering technique as described in the "Methods" section hereinbelow.

The transparency of the composition of the present invention is unexpected because, in general, the phospholipids give a dispersion in water that is white or opalescent in direct proportion to their concentration; the phenomenon of opalescence is encountered even at low concentrations (0.06 mg/ml).

At the moment of preparation, the composition of the invention may also be opalescent but, surprisingly, it becomes substantially transparent upon sterilization under heating.

The reasons why the said heating gives a dispersion that is substantially transparent and remains so for a long time after it has been cooled have not yet been elucidated but it is conjectured that heating promotes the formation of transparent liquid crystals.

Heating at lower temperatures (50-60°C), even for an hour and a half, did not eliminate the opalescence. In a second aspect, the present invention relates therefore to a sterile aqueous ophthalmic composition characterized in that it is obtained by

- adding a lyotropic mesomorphic lipid and a pegylated derivative of a lyotropic mesomorphic lipid to water, and

- sterilizing the thus obtained aqueous composition via heating. Advantageously said sterilization step is performed at 110-130°C for at least 15 minutes. Preferably, at approximately 120°C for 20 minutes.

Typically, the thus obtained composition has at least one of the following features:

- is substantially free of particles having an average size larger than 30 nm,

Preferably, the said composition is substantially free of particles having an average size larger than 20 nm.

Typical examples of lyotropic mesomorphic lipids according to the present invention are: phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, phosphatidylserine, phosphatidylglycerol, ionized phosphatidic acid, cardiolipin, plasminogen, cerebrosides, monoglycerides, α-hydroxy acids, glycerol monoethers, glycolipids of animal origin, sulpholipids of animal or vegetable origin, and mixtures thereof.

In the present invention the neutral lipids, such as phosphatidylcholine (DMPC), phosphatidylethanolamine (DLPE) and sphingomyelin, are preferred to anionic ones, such as phosphatidic acid, phosphatidylserine, phosphatidylglycerol and phosphatidylinositol, because any traces of calcium salt-out the latter causing their precipitation with possible clouding of the dispersion. This drawback can, however, be avoided by adding a compound that is able to complex the calcium, for example EDTA. However, in its turn, EDTA has the drawback that it affects the characteristics of the Iacrimal film and has toxic effects at the corneal level (Furrer P. et al., Ocular tolerance of preservatives on the murine cornea, Eur. J. Pharm. Biopharm. 47: 105-112, 1999; Saarinen-Savolainen P. et al., Evaluation of cytotoxicity of various ophthalmic drugs, eye drop excipients and cyclodextrins in an immortalized human corneal epithelial cell line, Pharm. Res., 15: 1275-1280, 1998).

In its turn, the expression "pegylated derivative of a lyotropic mesomorphic lipid" indicates a lyotropic mesomorphic lipid, as defined above, derivatized using a polyethyleneglycol (PEG).

Preferably the lipid derivatized with a PEG is a phospholipid. Typically, it is phosphatidylethanolamine.

A typical example of pegylated derivative of a lyotropic mesomorphic lipid is phosphatidylethanolamine derivatized with PEG 2000, marketed by the company Lipoid, Ludwigshafen, Germany, with the name Lipoid™ PE PEG 2000™. Another example is the phosphatidylethanolamine derivatized with PEG 750 that is obtainable from the company Genzyme Pharmaceutical, Suffolk, UK.

Advantageously, the amount of lyotropic mesomorphic lipid in the composition of the present invention is less than or equal to 0.35 mg/ml, preferably it is less than or equal to 0.20 mg/ml, and even more preferably it is less than or equal to 0.15 mg/ml.

In its turn, the amount of pegylated derivative of a lyotropic mesomorphic lipid in the composition of the present invention is less than or equal to 5 mg/ml, preferably it is less than or equal to 2 mg/ml, and even more preferably it is less than or equal to 1 mg/ml.

The composition of the present invention can also contain other pharmaceutically acceptable components provided that their properties and their amounts are not such as to cause unacceptable impairment of the characteristics of the film formed by the ophthalmic composition of the invention. The said components can be either inert or pharmacologically active.

Examples of such components are: diluents, buffers, osmotic pressure regulating agents, preservatives, antibacterial agents, anti- inflammatory agents, antioxidants, vasoconstrictors, vasodilators, vitamins and the like.

Examples of suitable diluents are polyhydroxy aliphatic alcohols such as ethylene glycol and propylene glycol, glycerol and polyvinyl alcohol (PVA).

Examples of suitable buffers are phosphate buffers, tromethamine and glycine, capable of adjusting the pH between 5.5 and 7.5, preferably between 6.5 and 7.5.

Typical examples of suitable agents for adjusting osmotic pressure are sodium chloride, mannitol and trehalose. Preferably, the osmotic pressure of the composition according to the present invention is between 200 and 500 mOsmol/kg and, even more preferably, between 250 and 310 mOsmol/kg.

An example of a suitable pharmacologically active agent is pegylated vitamin E. A suitable pegylated vitamin E is vitamin E TPGS from Eastman (natural α-tocopherol derivatized with PEG 1000).

As is well known, vitamin E has antiradical and antioxidant properties. This therefore endows the composition of the present invention with the ability to protect the external structures of the eye from damage caused by free radicals and oxidants. Advantageously, the amount of vitamin E TPGS contained in the composition of the present invention is less than or equal to 10 mg/ml. Preferably, it is less than or equal to 5 mg/ml and, even more preferably, 2 mg/ml. The ophthalmic composition of the present invention can also contain other non-mesomorphic-lyotropic lipids provided that their properties and their amounts are not such as to impair the characteristics of the film formed by the ophthalmic composition of the invention.

For example, lysophosphatidylcholine (lysolecithin) and lysophosphatidylethanolamine seem to improve the fluidity of the lipid layer that forms when the composition of the invention is in contact with the cornea but also make the said layer less stable.

Thus it was determined that the preferred amount of lysophosphatidylcholine and lysophosphatidylethanolamine in the composition of the present invention is less than or equal to 3% (w/v) and, respectively, to 0.5% (w/v) relative to the total amount of non- pegylated lyotropic mesomorphic lipid.

It was also determined that the composition of the present invention can contain concentrations of triglycerides up to 3% (w/v) relative to the total amount of non-pegylated lyotropic mesomorphic lipid.

As well as forming a stable film made up of a lipid layer and an aqueous layer, the ophthalmic composition of the present invention also possesses the following advantages: low surface tension, non- Newtonian viscosity and good transparency. In addition, it can be sterilized easily and is well tolerated by the eye.

The ability of a liquid to spread is greater the lower its surface tension.

The surface tension of the composition of the present invention is low, like that of natural Iacrimal fluid (< 46 mN/m at 32°C). Furthermore, it is < 47 mN/m at 25°C. Therefore the ability of the ophthalmic composition of the present invention to spread and be distributed in the eye is fully similar if not identical to that of the natural Iacrimal fluid.

With regard to viscosity, there is a widespread misunderstanding according to which a fluid should remain in the eye for a longer time the higher its viscosity, because a high viscosity should guarantee a high level of adherence.

On the contrary, the peculiar behaviour of natural Iacrimal fluid resides in the fact that its viscosity is of the non-Newtonian type. In fact, in the absence of shearing forces (small movements of the eyelids with the eye open), its viscosity is high enough to resist drainage by gravity, but it falls sharply when the shearing force increases (movement of the eyelids) thus preventing viscous drag and epithelial damage (J.M. Tiffany "The viscosity of human tears", Int. Ophthalmol., 15, 371-376, 1991).

The viscosity of the composition of the present invention also exhibits behaviour of the non-Newtonian type. More precisely, the composition of the present invention is viscoplastic with a yield point. Its Bingham viscosity is of from 1 to 5 cP, preferably from 1.5 to 2.5 cP, with yield point from 0.5 to 4 dyn/cm², preferably from 0.5 to 2.5 dyn/cm².

The following examples will help to illustrate the present invention without, however, limiting it.

Experimental Section Materials Component A

Commercial mixture (Lipoid™ E80 from Lipoid, Ludwigshafen, Germany) comprising:

Phosphatidylcholine 80-85% (w/v), Phosphatidylethanolamine 7.0-9.5% (w/v), Lysophosphatidylcholine < 3% (w/v), Lysophosphatidylethanolamine < 0.5% (w/v), Sphingomyelin < 3% (w/v), and Triglycerides < 3% (w/v). Component B Phosphatidylethanolamine derivatized with PEG 2000 (Lipoid™

PEG2000 from Lipoid, Ludwigshafen, Germany). Component C

Phosphatidylethanolamine derivatized with PEG 750 (Lipoid™ PEG750 from Genzyme Pharmaceutical, Suffolk, UK). Component D

Phosphatidylethanolamine derivatized with PEG 5000 (Lipoid™ PEG5000 from Genzyme Pharmaceutical, Suffolk, UK). Component E

Natural α-tocopherol derivatized with PEG 1000 (Vitamin E TPGS from Eastman Chemical Company Corporate, Kingsport, TN, USA)

Methods Surface tension

This was determined with a type TE-1 C™ tensiometer equipped with a type RC6-CS thermostatic bath from Lauda, Germany. The measurements were taken at 25 and at 32°C by the During-

Nouy ring method. Bingham viscosity

This was determined with a CSL™ 500 cone rheometer from Carri- Med (Dorking, UK) with a cone-plate configuration: acrylic cone, diameter 6 cm; cone angle: 2°; distance between cone and plate: 72 μm. The measurements were taken at 20°C by the controlled stress technique in which the force is applied to the test sample gradually and linearly for 3 minutes (1 minute ascend time, 1 minute peak hold time, 1 minute descend time) starting from a shear stress of 0 dyn/cm² up to 20 dyn/cm².

The behaviour of all the samples was of the viscoplastic type and satisfied the well-known Bingham equation. In particular, they exhibited a yield point beyond their behaviour as elastic materials.

The same apparatus also provides the values of the yield point. Qsmolaritv

This was determined with a "Semi-micro Osmometer Type Digital/L code A300" automatic osmometer from Knauer (Germany), which measures the depression of the freezing point. Light scattering

This was determined with a Nicomp™ 370 device from Particle Sizing Systems, Santa Barbara, CA, USA.

The method is based on measurement of the intensity (kHz) of a laser beam (5 nW HeNe) reflected at 90° from the sample contained in a standard cuvette having an optical path of 1 cm and maintained at 23°C.

The measured value is greater the more particles there are in the sample. Example 1

Comparative Composition 1 Materials Component A 6 mg

NaH₂P0₄ H₂0 20 mg Na₂HP0₄-12H₂0 56 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Miili-Q) to 100 ml

Component A was dispersed in hot water (25 ml) at approx. 50-60°C with vigorous magnetic stirring for at least 1 hour. Glycerol, and water up to 95 ml, were added to the dispersion thus obtained.

The dispersion was stirred vigorously over night. The sodium phosphates and the sodium chloride were added, while stirring, to the opalescent dispersion thus obtained.

The dispersion was adjusted to a volume of 100 with water and stirring was continued for 1 hour.

Finally, the opalescent dispersion was sterilized by heating to 120°C for at least 20 minutes first. The dispersion thus obtained was still opalescent and had the following properties:

Surface tension at 25°C: 56.52 mN/m; Surface tension at 32°C: 52.52 mN/m; Viscosity: 1.6 cP; Yield point: 0.75 dyn/cm².

Example 2

Comparative Composition

Materials

Component B 25 mg

NaH₂P0₄Η₂0 20 mg

Na₂HP0₄-12H₂0 56 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Milli-Q) to 100 ml The procedure followed was the same as in Example 1.

The dispersion thus obtained was substantially transparent to light scattering before and after sterilization and had the following properties:

Surface tension at 25°C: 57.57 mN/m;

Surface tension at 32°C: 54.42 mN/m; Bingham viscosity: 1.8 cP; Yield point: 0.85 dyn/cm².

Example 3

Composit ion A of the Invention

Materials

Component A 6 mg

Component B 25 mg

NaH₂P0₄ H₂0 20 mg

Na₂HP0₄-12H₂0 56 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

The procedure followed was the same as in Example 1. The dispersion thus obtained was opalescent (light scattering > 300 kHz; average particle size: 729.6 nm) before but substantially transparent after sterilization (light scattering < 20 kHz; average particle size: 18 nm) and had the following properties: Surface tension at 25°C: 42.44 mN/m; Surface tension at 32°C: 41.55 mN/m; Bingham viscosity: 1.92 cP; Yield point: 1.056 dyn/cm². pH = 6.77;

Osmolarity: 291 mOsm/kg.

As can be seen, the presence of both the Components A and B causes a considerable decrease in surface tension and a favourable increase in yield point relative to the Comparative Compositions 1 and 2, which contain the same amounts of Component A and, respectively, of Component B.

After 3 months at room temperature the dispersion was still substantially transparent to light scattering and had the following properties: Surface tension at 32°C: 43.38 mN/m;

Bingham viscosity: 1.92 cP;

Yield point: 1.056 dyn/cm². pH = 6.75;

Osmolarity: 295 mOsm/kg.

Example 4 Composition B of the Invention

Materials Component A 6 mg Component B 25 mg NaH₂P0₄ H₂0 20 mg Na₂HP0₄-12H₂0 56 mg Glycerol 500 mg NaCI 700 mg Deionized water (Milli-Q) to 100 ml

The procedure followed was the same as in Example 1.

The dispersion thus obtained was opalescent before but substantially transparent to light scattering after sterilization and had the following properties:

Surface tension at 25°C: 45.89 mN/m;

Surface tension at 32°C: 44.44 mN/m;

Bingham viscosity: 1.94 cP;

Yield point: 0.716 dyn/cm².

Example 5

Comparative Composition

Materials

Component A 12 mg

NaH₂PO₄ H₂0 20 mg

Na₂HP0₄-12H₂0 56 mg

Glycerol 500 mg NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

The procedure followed was the same as in Example 1. The dispersion thus obtained was opalescent before and after sterilization and had the following properties: Surface tension at 25°C: 45.56 mN/m; Surface tension at 32°C: 40.13 mN/m; Bingham viscosity: 1.65 cP; Yield point: 0.76 dyn/cm². Example 6

Composition C of the Invent

Materials

Component A 12 mg

Component B 25 mg

NaH₂P0₄ H₂0 20 mg

Na₂HP0₄-12H₂0 56 mg

Glycerol 500 mg

NaCI 700 mg

Surface tension at 25°C: 46.80 mN/m; Surface tension at 32°C: 41.54 mN/m;

Bingham viscosity: 1.95 cP; Yield point: 1.080 dyn/cm²

As can be seen, the presence of the both the Components A and B causes a considerable decrease in surface tension and a favourable increase in yield point relative to the Comparative Compositions 3 and 2, which contain the same amounts of Component A and, respectively, of Component B.

Example 7 Composition D of the Invention

Materials Component A 12 mg Component C 25 mg NaH₂P0₄Η₂0 20 mg Na₂HP0₄-12H₂0 56 mg Glycerol 500 mg NaCI 700 mg Deionized water (Milli-Q) to 100 ml

The procedure followed was the same as in Example 1.

Surface tension at 25°C: 46.80 mN/m;

Surface tension at 32°C: 41.06 mN/m;

Bingham viscosity: 1.90 cP;

Yield point: 0.841 dyn/cm²

Example 8

Comparative Composition

Materials

Component A 18 mg

NaH₂P0₄-H₂0 20 mg

Na₂HP0₄-12H₂0 56 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

The procedure followed was the same as in Example 1. The dispersion thus obtained was opalescent before and after sterilization and had the following properties: Surface tension at 25°C: 44.30 mN/m; Surface tension at 32°C: 40.25 mN/m; Bingham viscosity: 1.67 cP;

Yield point: 0.79 dyn/cm².

Example 9

Comparative Composition

Materials

Component B 50 mg

NaH₂P0₄ H 0 20 mg

Na₂HPO₄-12H₂0 56 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

The procedure followed was the same as in Example 1. The dispersion thus obtained was substantially transparent to light scattering before and after sterilization and had the following properties: Surface tension at 25°C: 57.24 mN/m; Surface tension at 32°C: 53.80 mN/m; Bingham viscosity: 1.00 cP.

Example 10 Composition E of the Invention

Materials Component A 18 mg Component B 50 mg NaH₂PO₄ H₂0 20 mg Na₂HP0₄-12H₂0 56 mg Glycerol 500 mg NaCI 700 mg Deionized water (Milli-Q) to 100 ml

The procedure followed was the same as in Example 1. The dispersion thus obtained was opalescent before but substantially transparent to light scattering after sterilization and had the following properties:

Surface tension at 25°C: 41.13 mN/m; Surface tension at 32°C: 38.57 mN/m; Bingham viscosity: 1.90 cP; Yield point: 0.782 dyn/cm². As can be seen, the presence of the both the Components A and B causes a considerable decrease in surface tension relative to the Comparative Compositions 4 and 5, which contain the same amounts of Component A and, respectively, of Component B.

Example 11 Composition F of the Invention

Materials Component A 18 mg

Component C 50 mg

NaH₂P0₄Η₂0 20 mg Na₂HP0₄-12H₂0 56 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

Surface tension at 25°C: 41.23 mN/m; Surface tension at 32°C: 41.18 mN/m; Bingham viscosity: 1.95 cP; Yield point: 0.692 dyn/cn

Example 12

Comparative Composition 6

Materials

Component B 500 mg

NaH₂P0₄ H₂0 20 mg

Na₂HP0₄-12H₂0 56 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

The procedure followed was the same as in Example 1. The dispersion thus obtained was substantially transparent to light scattering before and after sterilization and had the following properties: Surface tension at 25°C: 56.07 mN/m; Surface tension at 32°C: 53.60 mN/m; Bingham viscosity: 1.8 cP;

Yield point: 0.85 dyn/cnr

Example 13

Composition G of the Invent

Materials

Component A 18 mg

Component B 500 mg

NaH₂P0₄ H₂0 20 mg

Na₂HP0₄-12H₂0 56 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

Surface tension at 25°C: 41.13 mN/m; Surface tension at 32°C: 40.00 mN/m;

Bingham viscosity: 2.0 cP; Yield point: 1.8 dyn/cm².

As can be seen, the presence of the both the Components A and B causes a considerable decrease in surface tension and a favourable increase in yield point relative to the Comparative Compositions 4 and 6, which contain the same amounts of Component A and, respectively, of Component B.

This example also shows that, beyond a certain limit, addition of further amounts of non-pegylated and pegylated lyotropic mesomorphic lipids no longer has an effect on the surface tension.

Example 14

Composition H of the Invenl

Materials

Component A 6 mg

Component B 25 mg

Component E 100 mg

NaH₂P0₄ H₂0 20 mg

Na₂HP0₄-12H₂0 86 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

The procedure followed was the same as in Example 1. The dispersion thus obtained was opalescent (light scattering > 300 kHz; average particle size: 701 nm) before but substantially transparent after sterilization (light scattering < 20 kHz; average particle size: 14.1 nm) and had the following properties:

Surface tension at 25°C: 40.26 mN/m;

Surface tension at 32°C: 38.66 mN/m; Bingham viscosity: 1.97 cP;

Yield point: 0.99 dyn/cm². pH = 6.93;

Osmolarity: 290 mOsm/kg;

Absorbance (measured at 400 nm in a cell of 0.2 mm): 0.0099; Absorbance (measured at 400 nm in a cell of 0.2 mm at 100X (w/v) dilution in deionized water): 0.0001.

After 3 months at room temperature the dispersion was still substantially transparent to light scattering and had the following properties: Surface tension at 32°C: 38.56 mN/m;

Bingham viscosity: 1.84 cP;

Yield point: 0.94 dyn/cm²; pH = 6.94;

Osmolarity: 301 mOsm/kg. Example 15

Composition I of the Inventi

Materials

Component A 12 mg

Component B 25 mg

Component E 100 mg

NaH₂P0₄ H₂0 20 mg

Na₂HP0₄-12H₂0 86 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Mill li-Q) to 100 ml The procedure followed was the same as in Example 1. The dispersion thus obtained was opalescent before but substantially transparent to light scattering after sterilization and had the following properties: Surface tension at 25°C: 41.60 mN/m;

Bingham viscosity: 1.98 cP; Yield point: 0.98 dyn/cm².

Example 16 Composition J of the Invention Materials

Component A 18 mg

Component B 25 mg

Component E 100 mg

NaH₂P0₄ H₂0 20 mg Na₂HP0₄-12H₂0 86 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

Surface tension at 25°C: 41.00 mN/m; Surface tension at 32°C: 39.50 mN/m; Bingham viscosity: 1.98 cP;

Yield point: 0.95 dyn/cm².

Example 17 Composition K of the Invention Materials Component A 6 mg Component B 12.5 mg

Component E 100 mg

NaH₂P0₄ H₂0 20 mg

Na₂HP0₄-12H₂0 86 mg

Glycerol 500 mg

NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

The procedure followed was the same as in Example 1. The dispersion thus obtained was opalescent (light scattering > 300 kHz; average particle size: 645.4 nm) before but substantially transparent after steπlization (light scattering < 20 kHz; average particle size: 12.9) and had the following properties: Surface tension at 25°C: 40.06 mN/m; Surface tension at 32°C: 39.60 mN/m; Bingham viscosity: 1.97 cP;

Yield point: 0.99 dyn/cm². pH = 6.97;

Osmolarity: 293 mOsm/kg; Light scattering < 20 kHz. After 3 months at room temperature the dispersion was still substantially transparent to light scattering and had the following properties:

Surface tension at 32°C: 39.07 mN/m; Bingham viscosity: 1.91 cP; pH = 6.96;

Osmolarity: 297 mOsm/kg.

Example 18 Composition L of the Invention Materials Component A 12 mg Component B 12.5 mg

Component E 100 mg

NaH₂P0₄ H₂0 20 mg

Na₂HP0₄-12H₂0 86 mg Glycerol 500 mg

NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

Surface tension at 25°C: 40.02 mN/m; Surface tension at 32°C: 39.85 mN/m; Bingham viscosity: 2.00 cP; Yield point: 0.97 dyn/cm²

Example 19 Composition M of the Invention Materials Component A 18 mg Component B 12.5 mg

Component E 100 mg

NaH₂P0₄Η₂0 20 mg

Na₂HP0₄-12H₂0 86 mg

Glycerol 500 mg NaCI 700 mg

Deionized water (Milli-Q) to 100 ml

The procedure followed was the same as in Example 1. The dispersion thus obtained was opalescent before but substantially transparent to light scattering after sterilization and had the following properties: Surface tension at 25°C: 41.13 mN/m; Surface tension at 32°C: 39.60 mN/m; Bingham viscosity: 2.1 cP; Yield point: 0.94 dyn/cm².

Claims

1. An aqueous ophthalmic composition, characterized in that it comprises a lyotropic mesomorphic lipid and a pegylated derivative of a lyotropic mesomorphic lipid and in that it is substantially transparent.

2. A sterile aqueous ophthalmic composition characterized in that it is obtained by

- adding a lyotropic mesomorphic lipid and a pegylated derivative of a lyotropic mesomorphic lipid to water, and - sterilizing the thus obtained aqueous composition via heating.

3. A composition according to Claim 1 or 2, characterized in that it has at least one of the following features:

- is substantially free of particles having an average size larger than 30 nm, - has an absorbance (measured at 400 nm) of less than 0,05 when it is not diluted and less than 0,001 at 100X (w/v) dilution in deionized water.

4. A composition according to Claim 3, characterized in that it is substantially free of particles having an average size larger than 20 nm.

5. A composition according to any one of the preceding Claims 1 to 4, characterized in that the lyotropic mesomorphic lipid is selected from the group comprising phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, phosphatidylserine, phosphatidylglycerol, ionized phosphatidic acid, cardiolipin, plasminogen, cerebrosides, monoglycerides, α-hydroxy acids, glycerol monoethers, glycolipids of animal origin, sulpholipids of animal or vegetable origin, and mixtures thereof.

6. A composition according to Claim 5, characterized in that the lyotropic mesomorphic lipid is phosphatidylcholine, phosphatidylethanolamine or a mixture thereof.

7. A composition according to any one of the preceding Claims 1 to 6, characterized in that the pegylated derivative of a lyotropic mesomorphic lipid is selected from the group comprising phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, phosphatidylserine, phosphatidylglycerol, ionized phosphatidic acid, cardiolipin, plasminogen, cerebrosides, monoglycerides, α-hydroxy acids, glycerol monoethers, glycolipids of animal origin, sulpholipids of animal or vegetable origin, and mixtures thereof derivatized with a polyethyleneglycol.

8. A composition according to Claim 7, characterized in that the pegylated derivative of a lyotropic mesomorphic lipid is the phosphatidylethanolamine derivatized with PEG 2000.

9. A composition according to Claim 7, characterized in that the pegylated derivative of a lyotropic mesomorphic lipid is the phosphatidylethanolamine derivatized with PEG 750.

10. A composition according to any one of the preceding Claims 1 to 9, characterized in that the amount of lyotropic mesomorphic lipid is less than or equal to 0.35 mg/ml.

11. A composition according to any one of the preceding Claims 1 to

10, characterized in that the amount of lyotropic mesomorphic lipid is less than or equal to 0.20 mg/ml.

12. A composition according to any one of the preceding Claims 1 to

11 , characterized in that the amount of lyotropic mesomorphic lipid is less than or equal to 0.15 mg/ml.

13. A composition according to any one of the preceding Claims 1 to 12, characterized in that the amount of pegylated derivative of a lyotropic mesomorphic lipid is less than or equal to 5 mg/ml.

14. A composition according to any one of the preceding Claims 1 to 13, characterized in that the amount of pegylated derivative of a lyotropic mesomorphic lipid is less than or equal to 2 mg/ml.

15. A composition according to any one of the preceding Claims 1 to

14, characterized in that the amount of pegylated derivative of a lyotropic mesomorphic lipid is less than or equal to 1 mg/ml.

16. A composition according to any one of the preceding Claims 1 to

15, characterized in that it also comprises a diluent consisting of a polyhydroxy aliphatic alcohol.

17. A composition according to Claim 16, characterized in that the diluent is glycerol.

18. A composition according to any one of the preceding Claims 1 to 17, characterized in that it also comprises a buffer adjusting pH between 5.5 and 7.5.

19. A composition according to Claim 18, characterized in that the pH is adjusted between 6.5 and 7.5.

20. A composition according to any one of the preceding Claims 1 to 19, characterized in that it also comprises an agent adjusting osmotic pressure between 200 and 500 mOsmol/kg.

21. A composition according to Claim 20, characterized in that the osmotic pressure is adjusted between 250 and 310 mOsmol/kg.

22. A composition according to any one of the preceding Claims 1 to 21 , characterized in that it is an artificial tear.

23. A composition according to any one of the preceding Claims 1 to 21 , characterized in that it further comprises a pharmacologically active compound.

24. A composition according to Claim 23, characterized in that the said pharmacologically active compound is derivatized with a polyethyleneglycol.

25. A composition according to Claim 23 or 24, characterized in that the said pharmacologically active compound is selected from the group comprising antibacterial agents, anti-inflammatory agents, antioxidants, vasoconstrictors, vasodilators and vitamins.

26. A composition according to Claim 24, characterized in that the said pharmacologically active compound is vitamin E derivatized with PEG 1000.

27. A composition according to Claim 26, characterized in that it contains a amount less than or equal to 2 mg/ml of vitamin E derivatized with PEG 1000.

28. A composition according to any one of the preceding Claims 1 to 27, characterized in that it has a surface tension < 47 mN/m at

25°C.

29. A composition according to any one of the preceding Claims 1 to 27, characterized in that it has a surface tension < 46 mN/m at 32°C.

30. A composition according to any one of the preceding Claims 1 to 29, characterized in that it has a Bingham viscosity of from 1 to 5 cP.

31. A composition according to Claim 30, characterized in that it has a Bingham viscosity of from 1.5 to 2.5 cP.

32. A composition according to any one of the preceding Claims 1 to

31 , characterized in that it has a yield point of from 0.5 to 4 dyn/cm².

33. A composition according to Claim 32, characterized in that it has a yield point of from 0.5 to 2.5 dyn/cm².