BE1030504A1 - COMPOSITE INSERT FOR THE TREATMENT OF DRY EYE - Google Patents

Abstract

A bioresorbable ophthalmic insert comprising at least 25% by mass of a first cellulose derivative being hydroxypropyl cellulose (HPC), said HPC having a molecular mass of between 800,000 and 120,000 Da, and between 1 and 75% by mass of a viscosity agent consisting of sodium hyaluronate, or a second cellulose derivative different from the first cellulose derivative and manufacturing processes by extrusion or molding.

Description

COMPOSITE INSERT FOR THE TREATMENT OF DRY EYE

Technical field

The present invention relates to ophthalmic inserts and more particularly those for the treatment of dry eye.

Prior art

Dry eye syndrome, also called dry eye syndrome or keratoconjunctivitis sicca, although it seems trivial, represents, in practice, a poorly resolved problem which strongly affects the quality of life of affected patients, this disease, untreated, may also lead to blindness.

The disease is multifactorial and is reflected by poor homeostasis of the tear film, its instability, its hypertonic character, by inflammation and damage to the ocular surface, and by

Aberrant nervous sensitivity.

Two causes are recognized, insufficient tear production and excessive evaporation, the second being much more widespread.

Current treatments include, among others, the application of artificial tears, corticosteroids or even immunosuppressive agents (e.g. Cyclosporine A), administered in the form of drops.

However, these treatments are cumbersome over time. In particular, when the disease is at a more advanced stage, the application of drops several times a day is necessary, for example 6 times, which is particularly delicate for very elderly people, while the disease at its advanced stage is often found in older people.

Rather than drops to be applied regularly, inserts based on bioresorbable hydrophilic polymers have been developed in the past and marketed.

Patent US3845201 describes an insert based on alginate in synergy with pilocarpine.

Patent US4343787 describes an insert based on hydroxypropyl cellulose (HPC) for the treatment of dry eyes. || This is a patent covering an insert which was marketed under the name

Lacrisert®.

Patent GB1485149 also describes an insert based on HPC and reinforced with an active agent.

Patent US4730013 describes an insert based on hydroxypropyl methyl cellulose (HPMC), or HPC, which can include compounds such as polyvinyl alcohol, mannitol or glycerin. The goal is to reduce the phenomenon of blurred vision, which is all too common when applying Lacrisert®.

Patent US6217896 describes the advantage associated with a particular insert geometry.

These various publications show, in fact, that the best product that has been developed is Lacrisert®, and that various approaches have been tried to correct the main limitation, but without tangible success.

Brief summary of the invention

A first aspect of the present invention relates to a bioresorbable ophthalmic insert comprising at least: - 25%, preferably at least 30%, preferably at least 40%, or even at least 50% by mass of a first cellulose derivative being a hydroxypropyl cellulose (HPC), said HPC having a molecular mass of between 800,000 and 1200,000 Da, and - between 10 and 75% by mass of a viscosity agent, being sodium hyaluronate, and/or a second derivative of cellulose different from the first cellulose derivative, said second cellulose derivative being chosen from an HPC of molecular mass different from that of the HPC of the first cellulose derivative, hydroxypropyl methyl cellulose (HPMC), carboxy-methyl cellulose (CMC), methyl cellulose and their mixtures.

Advantageously, this insert further comprises a functional molecule chosen from the group consisting of L-carnitine, betaine, trehalose, erythritol and their mixtures, preferably between 2 and 40%, preferably between 3 and 30%, preferably between 4 and 20%, preferably between 5 and 15% by mass of the functional molecule.

Advantageously, this ophthalmic insert comprises both sodium hyaluronate and trehalose, preferably at least 1% (at least 2%, at least 5%, for example approximately 10%) by mass of sodium hyaluronate and at least 1% by mass of trehalose (at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or even approximately 30% by mass of trehalose).

Advantageously, the viscosity agent is present in the insert at a mass content of between 10 and 50%, preferably between 15% and 40%, preferably between 20 and 30% (sum of the masses of the viscosity agents: mass total of the insert).

Advantageously, the second cellulose derivative is an HPC having a molecular mass of between 100,000 and 750,000 Da, preferably between 200,000 and 700,000 Da, preferably between 300,000 and 500,000 Da, or an HPC having a molecular mass of between 1300,000 and 2500,000 Da. .

A related aspect of the present invention is a process for the manufacture of the above insert in which: - ON Mixes at least 25% by mass of hydroxypropyl cellulose (HPC), said HPC having a molecular mass of between 800,000 and 1200000 Da, and between 10 and 75% by mass of a viscosity agent being a second cellulose derivative different from the first cellulose derivative and/or sodium hyaluronate, this mixture is extruded at a temperature below 200°C, then the structure obtained is cut to obtain inserts of the desired dimensions.

Preferably this process results in an insert having the shape of a cylinder or an elliptical cylinder, preferably said cylinder having a diameter less than 2 mm (or less than 1.5 mm, or less than 1 mm) and a length less than 7 mm (or less than 6 mm or less than 5 mm or less than 4 mm, or even 3 mm), said elliptical cylinder having a length less than 7 mm (or less than 6 mm or less than 5 mm or less than 4 mm, or even 3 mm) and the major axis less than 2 mm (or less than 1.5 mm, or less than 1 mm).

A related aspect of the present invention is an alternative process for manufacturing the insert in which at least 25% by weight of hydroxypropyl cellulose (HPC) is mixed, said HPC having a molecular mass of between 800,000 and 1200,000 Da, and between 10 and 75% by mass of a viscosity agent being a second cellulose derivative different from the first cellulose derivative and/or sodium hyaluronate, an injection of this mixture is carried out at a temperature lower than 5 to 200° C in a mold of desired geometry.

Preferably this process results in an insert having the shape of an ellipsoid, a cylinder or an elliptical cylinder with hemispherical ends (grain of rice), preferably the major axis of the ellipsoid, the length of the cylinder or the length of the elliptical cylinder having a size less than 7 mm (or less than 6 MM or less than 5 MM or less than 4 mm, or even 3 mm) and, preferably the minor axis of the ellipsoid or the diameter of the cylinder or the major axis of the elliotic cylinder having a dimension less than 2 mm (or less than 1.5 mm, or less than 1 mm).

Advantageously, these processes include the additional step of sterilizing the insert by irradiation with gamma rays.

Detailed description of an embodiment of the invention

The inventors noticed that the problems of simple inserts made of hydroxypropyl cellulose (HPC) could be overcome through the association with other derivatives intended to modify the viscosity (hereinafter described as "viscosity agent") for example other cellulose derivatives and/or hyaluronate (sodium/hyaluronic acid) to maintain a high local viscosity, while slowing down the resorption of the insert.

In the context of the present invention, the term "oohthalmic insert" is preferably understood to mean a sterile solid or semi-solid structure of appropriate size and shape, intended to be inserted into the conjunctival cul-de-sac for an action on the eye. Advantageously, such inserts have a mass of a few milligrams, for example between 1 and 50 milligrams, preferably between 2 and 40 milligrams, or between 3 and 30 milligrams, or between 4 and 20 milligrams or between 5 and 10 milligrams and, preferably, an elongated structure (cylinder, rod), which can be curved, domed or rounded at the ends.

Thus, A first aspect of the present invention relates to a bioresorbable ophthalmic insert comprising at least 25% (preferably at least 30% 40.50%) by mass of a first cellulose derivative, being hydroxypropyl cellulose (HPC) , said HPC having a molecular mass of between 800,000 and 1200,000 Da, and between 10 and 75% by mass of a second cellulose derivative different from the first cellulose derivative, said second cellulose derivative being chosen from an HPC of different molecular mass , hydroxypropyl methyl cellulose (HPMC), carboxy-methyl cellulose (CMC), methyl cellulose and mixtures thereof. Alternatively, the second cellulose derivative can advantageously be substituted, partially or totally, by hyaluronic acid and/or a hyaluronate, for example sodium hyaluronate. In the context of the present invention, in addition to sodium hyalyronate, salts of hyaluronate with other cations are possible, provided that the salt remains sufficiently soluble in the tear fluid (water) and is not toxic. Likewise, certain residues can be protonated, so that the terminology “sodium hyaluronate” covers, in the context of the present invention, hyaluronic acid. When mass contents are associated with hyaluronate or hyaluronic acid, these are preferably expressed in sodium hyaluronate equivalents.

In the context of the present invention, the degree of substitution of the HPC is preferably greater than 1, preferably greater than 2, preferably greater than or equal to 2.5 (approximately) or even greater, for example greater or equal to approximately 3, or even greater than or equal to approximately 4: number of hydroxypropyl molecules per glucose residue. A number greater than 2.5 means that certain hydroxypropyl residues have been grafted onto other hydroxypropyl residues, and not directly onto the glucose chain forming the cellulose.

In the context of the present invention, advantageously, the second cellulose derivative and the hyaluronic acid/hyaluronate are viscosity agents, preferably conferring a non-Newtonian fluid property to the tear film. This makes it possible to control the viscosity at the eye level, but also the kinetics of resorption of the insert. Indeed, the inventors have noticed that the use of the first cellulose derivative, HPC of the size described above, represents a compromise capable of reducing as much as possible the phenomenon of “blurred vision”. However, a more marked reduction is not possible, even by optimizing the physicochemical characteristics of the first cellulose derivative, unlike the incorporation of a second cellulose derivative and/or sodium hyaluronate. .

Preferably, the second cellulose derivative and/or sodium hyaluronate is present at a mass content of between 10 and 60%, preferably between 15% and 50%, preferably between 20 and 40%, for example between 25% and 50%. and 30%. Indeed, too high contents dilute the HPC content, or even the functional molecule content if it is present (see below), while too low contents will not allow sufficient improvement.

Preferably the viscosity agent comprises Hyaluronate (at least 1% by mass, at least 5% by mass, for example approximately 10% by mass; mass in sodium hyaluronate equivalent: total mass of the insert) and a second cellulose derivative (at least 10% by mass, or even at least 20% by mass).

This second cellulose derivative is advantageously present when the HPC having a molecular mass of between 800,000 and 1200,000 Da is only incorporated into the insert in proportions of between 25 and 50% by mass. Preferably VHPC having a molecular mass between 800,000 and 1200,000 Da and the second cellulose derivative together make up at least 50% of the mass of the insert, for example approximately 60%.

Thus, preferably, the insert comprises at least 25% of the first cellulose derivative and at least 25% of the second cellulose derivative, or at least 30% of the first cellulose derivative and at least 20% of the second cellulose derivative, or at least 35% of the first cellulose derivative and at least 15% of the second cellulose derivative, or at least 40% of the first cellulose derivative and at least 10% of the second cellulose derivative (mass percentages).

Preferably, the first and the second cellulose derivative are two HPCs, the first therefore having a molecular mass of between 800,000 and 1200,000 Da. This mixture with HPCs of smaller molecular mass and/or with HPCs of higher molecular mass, allows prolonged activity, and prevents the phenomenon of “blurred vision” from being too marked.

Preferably, when the second cellulose derivative is HPC, this has a molecular mass of between 100,000 and 750,000.

Da, preferably between 200,000 and 700,000 Da, preferably between 300,000 and 500,000 Da.

Alternatively, preferably, when the second cellulose derivative is HPC, the latter has a molecular mass of between 1300000 and 2500000 Da.

Alternatively, the second advantageous cellulose derivative is an HPMC. The preferred HPMCs have a degree of methoxy substitution (DE) of between 20 and 30% (number of -OH residues of glucose monomers substituted by a methyl group: total number of -OH residues of glucose monomers), for example between 22 and 29% and/or a degree of hydroxypropyl substitution (DH) of between 6 and 10%, for example 8% (number of -OH residues of glucose monomers substituted by a hydroxypropyl group: total number of residues -

OH of glucose monomers). Depending on the molecular weight and degree of substitution, a reasonably high viscosity can be achieved in the patient's eye, while delaying resorption of the insert.

Thus, an HPMC having a viscosity of 4000 mPa.s (2%, by mass in an aqueous solution, 25°C) or lower is advantageous, for example a viscosity less than 1000, or even less than 500 mPa.s.

Likewise HPMCs having a DE of about 29% and a DH of about 10% are preferred. Alternatively, HPMCs (of higher molecular weight) having a DE of 22% and a DH of 8% are advantageous.

Preferably, the insert comprising the first cellulose derivative (HPC with a molecular mass of between 800,000 and 1200,000) and the viscosity agent (the second cellulose derivative and/or sodium hyaluronate) further comprises between 1 and 40% by mass of a functional molecule chosen from the group consisting of L-carnitine, betaine, trehalose (a-a trehalose), erythritol and mixtures thereof.

These functional molecules are not easy to incorporate into an insert consisting essentially of cellulose derivatives, due to the high temperatures encountered during the manufacturing process, but also because it is difficult to incorporate them into these small inserts in a homogeneous manner.

However, unlike drops, the inventors have noticed that the addition of a functional molecule, for example trehalose, ideally more than 1% by mass of trehalose (preferably at least 2, 3, 4, 5, 10, 15 %), allowed increased and/or prolonged effectiveness for the patient. In turn, this allowed less frequent application of Vinsert, or the application of smaller inserts, which further reduces the known deleterious effects of “blurred vision”.

The inventors consider that the addition of a functional molecule described above, or even a mixture, can provide an osmo-protective character to the insert which is particularly advantageous.

Thus, preferably, the ophthalmic insert comprises between 2 and 40%, preferably between 3 and 30%, preferably between 4 and 20%, preferably between 5 and 15% by mass of the functional molecule or a mixture of functional molecules.

The preferred functional molecule is a-a trehalose (dinitrated).

In the context of the present invention, trehalose is preferably a-a trehalose at any degree of hydration, preferably a-a trehalose dihydrate. However, in the context of the present invention, the mass percentages are advantageously expressed by relating the trehalose equivalents to a-a trehalose dihydrate (even if, in practice, a-a trehalose at other degrees of hydration (or anhydrous ) is potentially present in insert).

Preferably, the functional molecule (trehalose; a-a trehalose) is incorporated in a mass content of at least 5%, preferably at least 10, 15, 20, 25, or even approximately 30%: mass of (a-a trehalose dihydrate: total mass of the insert).

Advantageously, the oohthalmic insert comprises both sodium hyaluronate and trehalose, preferably at least 1% (preferably at least 2, 3, 4, 5, or even approximately 10%) by mass of sodium hyaluronate. sodium and at least 1% (preferably at least 2, 3, 4, 5, 10, 15%) by mass of trehalose.

Preferably the insert has an elongated shape such as a stick, a cylinder, an elliptical cylinder or a deformed crescent-shaped cylinder. The insert can also be in the shape of a “grain of rice” (i.e. a stick whose ends are hemispherical in shape, rather than flat) or “rugby ball” (i.e. oval in shape, an ellipsoid).

The maximum dimension (length) is preferably less than 7 mm, preferably less than 5 mm, preferably less than 3 mm. In the context of a cylinder, the maximum dimension is preferably understood as the length. In the context of an ellipsoid, the maximum dimension is preferably understood as being the major axis. The secondary dimension is preferably understood as being the diameter of the cylinder or the major axis of the elliptical cylinder or the minor axis of Velipsoide. The secondary dimension is preferably less than 2 mm, preferably less than 1.5 mm, preferably less than 1 mm. In the case of a cylinder with hemispherical “grain of rice” ends, the main dimension is, preferably, the length of the cylinder increased by the sum of the two radii of the two terminal hemispheres.

Another aspect of the present invention relates to a process for manufacturing the insert described above in which at least 25% by weight of hydroxypropyl cellulose (HPC) is mixed, said

HPC having a molecular mass of between 800,000 and 1200,000 Da, and between 10 and 75% by mass of a viscosity agent being sodium hyaluronate and/or a second cellulose derivative different from the first cellulose derivative, we proceed to an extrusion of this mixture under determined temperature conditions compatible with the physicochemical properties of the functional molecules and/or viscosity agents, then the structure obtained is cut to obtain the insert to the desired dimensions.

A preferred shape of the insert obtained by extrusion is that of a cylinder or an elliptical cylinder. The dimensions are preferably as described above, namely preferably less than 7 mm, less than 5 mm or even less than 3 mm for the length and less than 2 mm, preferably less than 1.5 mm, of preferably less than 1 mm for the diameter or major axis of the ellipse of the elliptical cylinder.

Extrusion is advantageously carried out via a twin-screw system; a second extrusion via a single-screw system is advantageously carried out for better control of the physical properties of the future insert (homogeneity, second dimension).

Preferably, during extrusion, the temperature is kept as low as possible, i.e. at values lower than 250°C, preferably lower than 225°C, preferably lower than 200°C, preferably lower than 175°C. C, preferably lower than 150°C, or even lower than 125°C.

The cutting of the inserts is advantageously done in series, at the exit of the extrusion.

An alternative to extrusion is injection, which is advantageous for obtaining ellipsoid or “rice grain” shapes, even if the method is less automated. In this case, the components are mixed homogeneously (for example via twin screw extrusion) at temperatures maintained at values lower than 250°C, preferably lower than 225°C, preferably lower than 200°C, preferably lower than 175°C, preferably lower than 150°C, or even lower than 125°C, then this mixture is injected into the molds before cooling and solidification.

Preferably, the mold has a shape allowing an ellipsoid, a cylinder or an elliptical cylinder with hemispherical ends (grain of rice), preferably the major axis of the ellipsoid, the length of the cylinder or the length of the elliptical cylinder has a size less than 7 mm, preferably less than 5 mm, preferably less than 3 mm and, preferably the minor axis of the ellipsoid or the diameter of the cylinder or the major axis of the elliotic cylinder has a dimension less than 2 mm, preferably less than 1.5 mm, preferably less than 1 mm.

The process (extrusion or injection) may also include the step of curving the insert.

An additional sterilization step (extrusion or injection process) is advantageous. Among these, the use of ionizing radiation, such as gamma ray irradiation, is preferred.

Claims (12)

1. A bioresorbable ophthalmic insert comprising at least: - 25% by mass of a first cellulose derivative being a hydroxypropyl cellulose (HPC), said HPC having a molecular mass of between 800,000 and 1200,000 Da, and - between 10 and 75% by mass of a viscosity agent, being sodium hyaluronate, and/or a second cellulose derivative different from the first cellulose derivative, said second cellulose derivative being chosen from an HPC of different molecular mass, hydroxypropyl methyl -cellulose (HPMC), carboxy-methyl-cellulose (CMC), methyl cellulose and their mixtures. 2. The ophthalmic insert according to claim 1 further comprising a functional molecule chosen from the group consisting of L-carnitine, betaine, trehalose, erythritol and mixtures thereof 3. The ophthalmic insert according to claim 2 comprising between 2 and 40%, preferably between 3 and 30%, preferably between 4 and 20%, preferably between 5 and 15% by mass of the functional molecule. 4. The ophthalmic insert according to any one of the preceding claims comprising both sodium hyaluronate and trehalose, preferably at least 1% by weight of sodium hyaluronate and at least 1% by weight of trehalose. 5. The ophthalmic insert according to any one of the dependent claims, in which the viscosity agent is present at a mass content of between 10 and 50%, preferably between 15% and 40%, preferably between 20 and 30% ( sum of the masses of the viscosity agents: total mass of the insert). 6. The ophthalmic insert according to any one of the preceding claims in which the second cellulose derivative is an HPC having a molecular mass of between 100,000 and 750,000 Da, preferably between 200,000 and 700,000 Da, preferably between 300,000 and 500,000 Da. 7. The ophthalmic insert according to any one of the preceding claims in which the second cellulose derivative is an HPC having a molecular mass of between 1300000 and 2500000 Da. 8. A process for manufacturing the insert according to any one of the preceding claims in which at least 25% by weight of hydroxypropyl cellulose (HPC) is mixed, said HPC having a molecular mass of between 800,000 and 1200,000 Da, and between 10 and 75% by mass of a viscosity agent being A second cellulose derivative different from the first cellulose derivative and/or sodium hyaluronate, this mixture is extruded at a temperature below 200°C , then we cut the structure obtained to obtain inserts of the desired dimensions. 9. The method according to claim 8 in which the insert has the shape of a cylinder, an elliptical cylinder, preferably said cylinder having a diameter less than 2 mm and a length less than 7 mm, said elliptical cylinder having a length less than 7 mm and the major axis less than 2 mm. 10. A process for manufacturing the insert according to any one of preceding claims 1 to 7 in which at least 25% by weight of hydroxypropyl cellulose (HPC) is mixed, said HPC having a molecular mass of between 800,000 and 1200,000 Da , and between 10 and 75% by mass of a viscosity agent being A second cellulose derivative different from the first cellulose derivative and/or sodium hyaluronate, and an injection of this mixture is carried out at a lower temperature at 200°C in a mold of desired geometry. 11. The method according to claim 10, in which the geometry of the mold makes it possible to form an ellipsoid, a cylinder or an elliptical cylinder with hemispherical ends (grain of rice), preferably the major axis of the elliosoid, the length of the cylinder or the length of the elliptical cylinder having a size less than 7 mm and, preferably the minor axis of the elipsoid or the diameter of the cylinder or the major axis of the elliptical cylinder having a dimension less than 2 mm. 12. The method according to any one of preceding claims 8 to 11 comprising an additional step of sterilizing the insert by irradiation with gamma rays.