ITMI20090799A1 - COMPOSITION FOR OPHTHALMIC USE SUITABLE FOR THE TREATMENT OF THE INFLAMMATORY STATES OF THE EYE AND THE DRY EYE SYNDROME - Google Patents

Description

COMPOSITION FOR OPHTHALMIC USE SUITABLE FOR THE TREATMENT OF INFLAMMATORY STATES OF THE EYE AND DRY EYE SYNDROME

Description

The present invention relates to the use of compounds as active ingredients in a formulation for ophthalmic use suitable for the treatment of inflammatory states of the eye and dry eye syndrome, to be used in pharmaceutical compositions, medical-surgical devices, doctors and any other product suitable for ophthalmic use.

As is known, the tear film provides for the lubrication of the ocular surface and contributes to the growth and nourishment essential for the correct trophism of the corneal epithelium.

The optical quality of the external surface of the eye depends significantly on the characteristics of the lipid tear film, which in physiological conditions is such as to uniform the corneal surface, whose morphology is generally irregular and rough.

In addition to possessing refractive capabilities such as to contribute to correct vision and in addition to providing lubrication of the ocular surface, the tear film performs other specialized functions thanks to its complex composition. It consists of a mixture of proteins, mucins and electrolytes for maintaining the correct osmolarity and viscosity, antimicrobial substances, such as lactoferrin and lysozyme, growth factors that provide for trophism and regeneration of the corneal epithelium.

Lacrimal dysfunction is a multifactorial disease of the tears and ocular surface that causes ocular discomfort, visual disturbances and tear film instability, with potential damage to the ocular surface. This dysfunction is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.

In particular, in the case of the so-called dry eye syndrome, at the opening of the eyelid the lipid film takes a relatively long time to re-spread on the ocular surface and therefore forms interference bands that hinder correct vision.

All conditions that alter the characteristics of the ocular surface and the tear film induce hyperosmolarity and chronic inflammation. Inflammatory phenomena are a direct consequence of the increased osmolarity of the tear film and contribute to ocular damage and further tear dysfunction.

The integrity of the lipid film, and in particular of its external non-polar portion, is essential to prevent excessive evaporation of the tear secretion and must be the subject of targeted therapeutic interventions with suitable tear substitutes, such as, for example, between the most used are solutions of hyaluronic acid, of polymers such as polyacrylic acid, of cellulose derivatives.

Suitable tear substitutes and therapeutic agents for such dysfunctions must show a high biocompatibility even in prolonged administration, and must not induce toxic effects on the corneal epithelium in in vitro tests.

The object of the present invention is to provide suitable therapeutic agents for the treatment of the various states of alteration of the tear film as discussed above, and in particular of the inflammatory states of the eye and of the dry eye syndrome. For this purpose it proposes a compound of general formula (I):

wherein R-i, F3⁄4, R3, R4 = H; or linear or branched C1 to C4 alkyl; or, when R2, R3 are H, one between R-i and R4 = CO-R, where R = linear alkyl 0 branched from C3a C-ig

for the treatment of inflammatory states of the eye, including conjunctivitis, and dry eye syndrome, and pharmaceutical compositions, medical surgical aids or medical devices in general that contain said compounds, as such or in a mixture of them, as an active ingredient for ophthalmic use.

- The compound according to the above general formula in which R-i, R2, R3, R4 = H is 2.4-O-furfurilidenesorbitol, thus characterized:

Synonyms:

2.4-monofurfurylidene-sorbitol

D-Glucitol, 2, 4-0- (2-furanylmethylene) (CA INDEX NAME)

2,4 - furfuriliden sorbitol, or Furalglucitol, or Sorbitil Furfurale (INCI), or AR-GB11®

Formula

H /

C11H16O7

p.m. 260.24

CAS Registry #: [7089-59-0]

- Further compounds of the invention are the tetra alkyl ethers 2,4-0-furfurylidenesorbitol:

2,4-monofurfurylidene-1. 3. 5, 6-0-tetraalkylsorbitol

OR.

wherein Ri, R2IR3, R4 = linear or branched C-i to C4 alkyl.

Further compounds of the invention are the monoesters derived from furfurylidenesorbitol according to the above general formula, in which F3⁄4, F3⁄4 = H, and one between Ri and 3⁄4 = CO-R, in which R = alkyl linear or branched from C3a Cig, i.e .:

OH

In this class, one of the preferred compounds according to the invention is the octanoic acid ester, i.e. the following mono-octanoates, or a mixture thereof:

Still in this class, one of the preferred compounds according to the invention is an ester of a fatty acid, and in particular of paimitic acid, that is the following monopalmitates, or a mixture thereof:

The said monopalmitate, which is also identified under the brand AR-GG27®, due to the long chain of fatty acid acquires a remarkable lipophilicity which allows an ideal distribution within the oily phases that may be present in the formulations to be administer for ophthalmic use.

The use of the compounds of the above defined general formula according to the present invention is essentially based on the anti-inflammatory activity in ophthalmology, as well as on the protective activity against the cornea and on the repair of the corneal epithelium that they have shown to possess according to Io study described below.

Therapeutic applications are therefore envisaged in ophthalmology in the form of formulations for eye drops, ointments or other pharmaceutical forms suitable for administration in the eye, where the compounds of the invention suitably exert the said anti-inflammatory and restorative action.

These pharmaceutical forms preferably include solutions, suspensions, emulsions, microemulsions, ophthalmic ointments, ointments suitable for ophthalmic use. In the compositions of the invention, preferred concentration ranges in particular for the active principles ARGB11 2,4-O-furfurilidenesorbitoio, and ARGG272,4-O-furfurilidenesorbitol-monopalmitate, are the following: ARGB11 from 0.5 to 2% ww. ; ARGG27 from 0.1 to 1% p.p.

The main therapeutic applications envisaged are the treatment of inflammatory states of the eye, for example conjunctivitis, dry eye syndrome and in any case any inflammatory disorder or alteration of the physiological tear film.

Some examples of composition according to the present invention are described below. They must not be construed as limiting.

In these examples, the abbreviation ARGB11 identifies the compound 2,4-O-furfurylidenesorbed; the acronym ARGG27 identifies the compound 2,4-O-furfurylidenesorbitol-monopalmitate, and the quantities of the components are expressed as percentages by weight within a range, as specified below.

Example 1

Solution

Ingredient% p.p.

Purified water q.s. to 100

Hyaluronic acid sodium salt 0.01-0.05

ARGB11 0.5-2

Sodium Chloride 0.1-1

Potassium Chloride 0.1-1

Sodium monobasic phosphate monohydrate 0.01-0.2

Disodium phosphate dodecahydrate 0.01-0.2

Preservative to taste

Example 2

Solution

Ingredient% p.p.

Purified water q.s. a 100 ARGB11 0.5-2 Benzalkonium Chloride 0.01-0.2 Disodium edetate 0.01-0.2 Sodium chloride 0.1-1

Example 3

Microemulsion

Ingredient% p.p.

Purified water q.s. a 100 ARGB11 0.5-2 ARGG27 0.1-1 Monosodium phosphate 0.01-0.5 sodium sulphite heptahydrate 0.01-0.5 sodium chloride 0.1-1 benzalkonium chloride 0.01-0.2 hydroxypropylmethylcellulose 0.001-0.05 polysorbitan monooleate 0.1-0.5 Example 4

Microemulsion

Ingredient% p.p.

Purified water q.s. a 100 ARGB11 0.5-2 Tocopherol 0.1-1 Monosodium phosphate 0.01-0.5 sodium sulphite heptahydrate 0.01-0.5 sodium chloride 0.1-1 benzalkonium chloride 0.01-0.2 hydroxypropylmethylcellulose 0.001-0.05 polysorbitan monooleate 0.1-0.5

Example 5

Microemulsion

Ingredient% p.p.

Purified water q.s. a 100 ARGG27 0.1-1 Monosodium phosphate 0.01-0.5 sodium sulphite heptahydrate 0.01-0.5 sodium chloride 0.1-1 benzalkonium chloride 0.01-0.2 hydroxypropylmethylcellulose 0.001-0.05 polysorbitan monooleate 0.1-0.5 Example 6

Ophthalmic ointment

Ingredient% p.p.

ophthalmic vaseline to taste to 100

anhydrous lanolin 20

petroleum jelly 30

ARGG27 0.1-1

STUDY OF THE ACTIVITY OF COMPOUNDS ON THE CORNEAL EPITHELIUM

A very sensitive in vitro experimental model was used to test both the activity and the tolerability of the compounds according to the invention.

In particular, in the present study the following compounds of the invention were evaluated: furfurylidensorbitol (AR-GB11®) and furfurylidensorbitol-palmitate (AR-GG27®).

The experimental model is based on the in vitro three-dimensional reconstruction of the human corneal epithelium, starting from an immortalized cell line of corneal epithelium. A corneal epithelium of similar thickness and morphology identical to the natural one is obtained. The model thus obtained is extremely sensitive and is particularly suitable for pre-clinical studies after repeated applications.

In the present study this experimental model was used for two different purposes.

In the first part of the study, the long-term tolerability of the compounds of the invention furfurylidensorbitol (AR-GB11®) and furfurylidensorbitolopalmitate (AR-GG27®) was evaluated with respect to a comparison standard.

In the second part, the anti-inflammatory action and the effects on the tissue repair process were evaluated with respect to that comparison.

LONG-TERM TOLERABILITY

Both test compounds, furfurylidensorbitol (AR-GB11®) and furfurylidensorbitol-palmitate (AR-GG27®), were administered as microemulsions. They differ in that the first is very hydrophilic, while the second, as a consequence of the long aliphatic chain of paimitic acid, is mainly lipophilic.

The study involved the application of the two compounds under examination to the corneal epithelial tissue in vitro both at single and repeated doses (twice a day for several days), treating in parallel with comparison tear substitutes containing preservatives. A saline solution of 0.2% (w / v) polyacrylic acid, containing 0.01% (w / v) of benzalkonium chloride, was adopted as standard.

In fact, it is known that the administration of some eye drops, such as replacement or artificial tear compounds, has a negative action in the post-traumatic corneal re-epithelialization process, an action that is believed to be due to the presence of the preservative substances commonly used for these formulations. .

Using multiple endpoints, in order to increase the significance of the study, the following results were obtained:

- both single and chronic application of AR-GB11 and AR-GG27 did not cause evident alterations in cell viability, contrary to what was observed with the comparative tear substitutes, which reduced cell viability due to corresponding administration times;

- in the case of the tear substitutes of comparison, poorly tolerated by the cornea due to the presence of preservatives, necrotic cells and vacuoles were observed on histological examination, while no cell damage was observed in the tissues treated with AR-GB11 and AR-GG27

- no significant release of interleukin IL-1-alpha, a known proinflammatory cytokine, was shown after application of AR-GB11 and AR-GG27, contrary to what was observed with the comparative compounds for which it was noted a gradual increase in IL-1-alpha levels.

In summary, the results shown show that the compounds of the invention do not induce toxicity.

PARTIALLY DAMAGED HUMAN CORNEAL EPITHELIUM

In the second part of the study, the effects on the tissue repair process and the tolerability of AR-GB11 and AR-GG27 on partially damaged reconstituted human corneal epithelium were evaluated.

For this purpose, lesions were mechanically produced on the corneal tissue in vitro and subsequently the phenomena of inflammation and re-epithelialization were evaluated before and after the application of the compounds under examination.

The observed results were as follows:

- In the positive controls, immediately after the lesion there is the release of IL-1-alpha by the damaged tissues which is progressively reduced in the following hours. AR-GB11 and with AR-GG27 did not alter this trend, while the tear substitutes studied as a comparison slowed the reduction of IL-1-alpha.

- In tissues treated with AR-GB11 and with AR-GG27, no measurable amounts of TNF-alpha, a potent pro-inflammatory mediator, were detected, which was instead detected in significant quantities in tissues treated with comparator tear substitutes containing preservatives.

- The expression of the cell proliferation marker Ki-67 was quantified as an indication of a correct course of the re-epithelialization process. This expression was found significantly increased by the application of AR-GB11 and AR-GG27.

- None of the two compounds according to the invention inhibited the expression of integrin, a fundamental substance for migration phenomena in the times immediately following the injury.

- Control treatment with tear substitutes also induced an increase in the production of TGF-beta, a growth factor with profibrotic and antiproliferative action, an increase not observed with AR-GB11 and AR-GG27.

In conclusion, the experiments have shown for the compounds of the invention an anti-inflammatory and protective activity against the cornea;

Furthermore, these compounds, by counteracting the inflammatory responses resulting from trauma, favor the physiological process of corneal epithelial repair.

Claims (11)

Claims 1) Compounds of general formula (I) wherein R-i, R2, R3. R4 = H; or linear or branched C-ι to C4 alkyl; or, when R2, R3 are H, one of Ri and R4 = CO-R, wherein R = linear or branched alkyl from C3 to C19 for the treatment of inflammatory conditions of the eye and dry eye syndrome. 2) Compound according to claim 1 characterized in that it is 2,4-monofurfurylidene-sorbitol. 3) Compound according to claim 1 characterized in that it is 2,4-monofurfurylidene-1, 3,5,6-0-tetraalkylsorbitol wherein R-ι, R2, R3, R4 = linear or branched alkyl from C1 to C4. 4) Compound according to claim 1 characterized in that it is a monoester of 2,4-monofurfurylidene-sorbiteIo in which R2, R3 = H, and one of Ri and R4 = CO-R, in which R = linear or branched alkyl from C3a C19. 5) Compound according to claim 4 characterized in that it is octanoate monoester of 2,4-monofurfurylidene-sorbitol. 6) Compound according to claim 4 characterized in that it is palmitate monoester of 2,4-monofurfurylidene-sorbitol. 7) Use of a compound of general formula wherein Ri, R2, R3, R4 = H; or linear or branched C-ι to C4 alkyl; or, when R2, R3 are H, one between Ri and R4 = CO-R, in which R = linear or branched alkyl from C3 to C19, as such or in mixture with each other, in ophthalmology for the treatment of inflammatory states of the eye , dry eye syndrome and to promote the physiological process of corneal epithelial repair. 8) Use of at least one compound of general formula OR. wherein Ri, R2, R3, R4 = H; or linear or branched C-ι to C4 alkyl; or, when R2, R3 are H, one of Ri and R4 = CO-R, wherein R = linear or branched alkyl from C3 to C19 for the preparation of a pharmaceutical composition, a medical surgical device or a medical device for the treatment of inflammatory conditions of the eye, dry eye syndrome and to promote the physiological process of corneal epithelial repair. 9) Composition for pharmaceutical use or as a medical-surgical device or medical device or in other product for ophthalmic use for the treatment of inflammatory conditions of the eye, dry eye syndrome and to promote the physiological process of corneal epithelial repair , characterized in that it contains as active principle one or more of the compounds according to claim 1. 10. Composition according to claim 9 characterized in that it is formulated for ophthalmic use. 11) Composition according to claim 10 characterized in that it is formulated in solution, suspension, emulsion, microemulsion, such as eye drops, cream, ointment, ointment or other form suitable for ophthalmic use.