BE1030503A1 - INSERT FOR THE TREATMENT OF DRY EYE - Google Patents

Abstract

A bioresorbable ophthalmic insert comprising at least 25% by mass of hydroxypropyl cellulose (HPC), said HPC having a molecular mass greater than 500,000 Da, and between 1 and 50% by mass of a functional molecule chosen from the group consisting of sodium hyaluronate, L-carnitine, betaine, trehalose, erythritol and their mixtures and manufacturing processes by extrusion or molding.

Description

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, in practice represents a poorly resolved problem which strongly affects the quality of life of affected patients. This disease, if left untreated, risks leading 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 nerve sensitivity.

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

Current treatments include, among other things, the application of artificial tears of corticosteroids or immunosuppressive agents (e.g. Cyclosporine A) in solution, 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.

Among the solutions or drops to apply, we find solutions/drops including trehalose (3 g/100 ml) and sodium hyaluronate (0.15 g/100 ml). These two compounds are considered to impart protective, moisturizing and lubricating properties. A study aiming to compare hyaluronate alone or hyaluronate combined with trehalose did not, however, make it possible to conclude as to a synergistic effect associated with the addition of trehalose.

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

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 geometry of the insert.

These various publications show, in fact, that the best product that has been developed is Lacrisert®, and that various approaches have been tried to improve it, without major success.

Brief summary of the invention

A first aspect of the invention relates to a bioresorbable ophthalmic insert comprising at least 25% by mass of hydroxypropyl cellulose (HPC; it is a first cellulose derivative), said HPC having a molecular mass greater than 500,000 Da , and between 1 and 50% by mass of a functional molecule chosen from the group consisting of sodium hyaluronate, L-carnitine, betaine, trehalose, erythritol and mixtures thereof.

Advantageously, this 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.

Advantageously, this insert comprises both sodium hyaluronate and trehalose, preferably at least 1% by weight of sodium hyaluronate and at least 1% by weight of trehalose.

Advantageously, the HPC of this insert has a molecular mass of between 800,000 and 1200,000 Da.

Preferably, this insert comprises a second cellulose derivative, different from HPC having a molecular mass of between 800,000 and 1200,000 Da, 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.

Preferably this second cellulose derivative is incorporated into Vinsert in a mass content of between 10 and 35%, preferably between 15% and 30%, preferably between 20 and 25%.

Preferably, when the second cellulose derivative is incorporated and 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, or a mass molecular between 1300000 and 2500000 Da.

A related aspect of the present invention is a process for manufacturing the above insert in which: at least - 25% by mass of hydroxypropyl cellulose (HPC) is mixed, said

HPC having a molecular mass greater than 500,000 Da, and - between 1] and 50% by mass of a functional molecule chosen from the group consisting of L-carnitine, betaine, trehalose, sodium hyaluronate and their mixtures, as well as any other components, and this mixture is extruded at a temperature below 200°C, then insert is obtained.

Preferably this method allows the formation of the insert according to a cylinder, an elliptical cylinder or an arcuate 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 1mm).

An alternative to this related aspect of the invention is a process for manufacturing the above insert, in which at least - 25% by mass of hydroxypropyl cellulose (HPC) is mixed, said

HPC having a molecular mass greater than 500,000 Da, and - between 1] and 50% by mass of a functional molecule chosen from the group consisting of L-carnitine, betaine, trehalose, sodium hyaluronate and their mixtures, as well as any other components, and this mixture is injected at a temperature below 200°C into a mold of the desired geometry, then the insert is obtained.

Preferably, in this process, the shape of the mold allows an elipsoid, a cylinder or an elliptical cylinder with hemispherical ends (grain of rice), preferably the long 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 cylinder elliptical having a dimension less than 2 mm (or less than 1.5 mm or less than 1 mm).

Preferably, these methods include the additional step of carrying out the sterilization of Vinsert by gamma irradiation.

Detailed description of an embodiment of the invention

The inventors noticed that the problems of simple ophthalmic inserts made of hydroxypropyl cellulose (HPC) could be overcome by the addition of at least one functional molecule. These may be compounds having an osmoprotective action and/or compounds intended to modify viscosity (hereinafter described as “viscosity agent”).

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 oohthalmic insert comprising at least 25% by mass of hydroxypropyl cellulose (HPC; this is a first derivative of cellulose, see below), said HPC having a molecular mass greater than 500,000 Da, and between 1 and 50% by mass of a functional molecule chosen from the group consisting of sodium hyaluronate, L-carnitine, betaine, trehalose (a-a trehalose), erythritol and mixtures thereof.

In the context of the present invention, the degree of substitution of the HPC is preferably greater than 1, preferably greater than 2, preferably 2.5 (approximately) or even greater, for example approximately 3, or even greater. even around 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, 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 the insert).

These functional molecules are not easy to incorporate into an HPC insert, 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 noticed that the addition of trehalose, ideally more than 1% by weight of trehalose, allowed increased and/or prolonged effectiveness for the patient. In turn, this allowed less frequent application of the insert, or the application of smaller inserts, which further reduces the known deleterious effects of “blurred vision”.

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 weight of the functional molecule.

As described above, the inventors have noticed that the functional molecule, or a mixture of functional molecules described above, has an osmoprotective effect, which is advantageous.

The functional molecule can also be a viscosity agent.

In the context of the present invention, preferably, the terminology “viscosity agent” refers firstly to sodium hyaluronate and/or to the second cellulose derivative (see below). In the context of the present invention, in addition to hyaluronate

IO sodium, hyaluronate salts with other cations are possible, as long as 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 equivalent.

Advantageously, the oohthalmic insert comprises both sodium hyaluronate and trehalose, preferably at least 1% (preferably at least 2, 3, 4, 5, 10, 15%) 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 functional molecule (advantageously trehalose; a-a trehalose) is incorporated in a mass content of at least 5%, preferably at least 10, 15, 20, 25, 30, 35 or even approximately 40%: mass of the (a-a trehalose (dihydrate; see above for the calculation method according to the degree of hydration): total mass of the insert.

Preferably the sodium hyaluronate is incorporated in a mass content of at least 5%, preferably at least 10, 15, 20, 25, or even approximately 30%: mass of the sodium hyaluronate: total mass of the insert.

Preferably, the HPC (first cellulose derivative) has a molecular mass of between 800,000 and 1200,000 Da. This, compared to HPCs of smaller molecular mass and/or compared to HPCs of higher molecular mass, allows a somewhat prolonged effect, and prevents the phenomenon of “blurred vision” from being too marked.

Preferably, the ophthalmic insert comprises a second cellulose derivative different from HPC (first cellulose derivative) having a molecular mass of between 800,000 and 1200,000 Da, this 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. 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 the HPC 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).

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 HPC (first derivative of cellulose) only meeting the size described above represents a compromise capable of reducing as much as possible the phenomenon of “blurred vision”. However, the incorporation of other molecules such as second cellulose derivatives, functional molecules (osmo-protecting agents and/or viscosity agents) advantageously allows a more marked reduction of this annoying phenomenon.

Thus, 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 12%, preferably between 7 and 10%, for example (approximately) 8%, such as between 7.5 and 8.5% (number of -OH residues of glucose monomers substituted by a hydroxypropyl group: total number of -OH residues of glucose monomers). Depending on the molecular weight and degree of substitution, 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 HPMC in an aqueous solution, 25°C) or greater is advantageous. 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 second cellulose derivative is present at a mass content of between 10 and 35%, preferably between 15% and 30%, preferably between 20 and 25%. In fact, too high contents dilute the content of the first cellulose derivative (HPC), or even the functional molecule, while too low contents will not allow sufficient improvement.

Preferably, when the second cellulose derivative is

VHPC, this has a molecular mass 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.

Preferably the insert has an elongated shape such as a stick, a cylinder, an elliotic cylinder or a cylinder deformed in the shape of a crescent, the insert can also be in the shape of a "grain of rice" (therefore a stick whose ends are (substantially) hemispherical in shape, rather than flat) or “rugby ball” (hence 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 Velipsoid. 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 greater than 500,000 Da, and between 1 and 50% by mass of a functional molecule chosen from the group consisting of sodium hyaluronate, L-carnitine, betaine, trehalose and their mixtures, as well as any other components, and we carry out an extrusion of this mixture under determined temperature conditions compatible with the physico-chemical properties of the functional molecule(s), then we cut the structure obtained to obtain the insert with 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, these cylinders or elliotic cylinders being able to have 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 elipsoid or the diameter of the cylinder or the major axis of the elliptical cylinder has a dimension less than 2 mm, preferably less than 1.5 mm, preferably less than 1 mm.

The method may further include the step of applying an insert bend.

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

Claims (13)

1. A bioresorbable ophthalmic insert comprising at least: 25% by mass of hydroxypropyl cellulose (HPC), said HPC having a molecular mass greater than 500,000 Da, and between 1 and 50% by mass of a functional molecule chosen from the group consisting of sodium hyaluronate, L-carnitine, betaine, trehalose, erythritol and mixtures thereof. 2. The ophthalmic insert according to claim 1 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. 3. The ophthalmic insert according to claim 1 or 2 comprising both sodium hyaluronate and trehalose, preferably at least 1% by mass of sodium hyaluronate and at least 1% by mass of trehalose. 4. The ophthalmic insert according to any one of the preceding claims in which the HPC has a molecular mass of between 800,000 and 1200,000 Da. 5. The ophthalmic insert according to claim 4, comprising a second cellulose derivative, different from the first HPC having a molecular mass of between 800,000 and 1200,000 Da, said second cellulose derivative being chosen from an HPC of different molecular mass, the hydroxypropyl methyl cellulose (HPMC), carboxy-methyl cellulose (CMC), methyl cellulose and mixtures thereof. 6. The insert according to claim 5 in which the second cellulose derivative is present at a mass content of between 10 and 35%, preferably between 15 and 30%, preferably between 20 and 25%. 7. The insert according to claim 5 or 6 in which HPC being the second cellulose derivative 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. 8. The insert according to claim 5 or 6 in which HPC being the second cellulose derivative has a molecular mass of between 1300000 and 2500000 Da. 9. A process for manufacturing the insert according to any one of the preceding claims in which: - at least 25% by mass of hydroxypropyl cellulose (HPC) is mixed, said HPC having a molecular mass greater than 500,000 Da, and between 1 and 50% by mass of a functional molecule chosen from the group consisting of L-carnitine, betaine, trehalose, sodium hyaluronate and their mixtures, as well as any other components, and - this mixture is extruded at a temperature below 200°C. 10. The method according to claim 9 in which the insert has the shape of a cylinder, or an elliptical cylinder, preferably said cylinder having a diameter less than 2 mm and a length less than 7 mm or said elliptical cylinder having a length less than 7 mm and the major axis less than 2 mm. 11. A process for manufacturing the insert according to any one of preceding claims 1 to 8 in which: - at least 25% by mass of hydroxypropyl cellulose (HPC) is mixed, said HPC having a molecular mass greater than 500,000 Da , and between 1 and 50% by mass of a functional molecule chosen from the group consisting of L-carnitine, betaine, trehalose, sodium hyaluronate and their mixtures, as well as possible others components, and - this mixture is injected at a temperature below 200°C into a mold of the desired geometry. 12. The method according to claim 11, in which the geometry of the mold makes it possible to form an ellipsoid, a cylinder or an elliotic 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 Velipsoid or the diameter of the cylinder or the major axis of the elliotic cylinder having a dimension less than 2 mm. 13. The method according to any one of claims 9 to 12 comprising an additional step of sterilizing the insert by irradiation with gamma rays.