WO2008136034A2

WO2008136034A2 - Ophthalmic compositions for the treatment of ocular hypertension and glaucoma

Info

Publication number: WO2008136034A2
Application number: PCT/IT2008/000299
Authority: WO
Inventors: Daniele Sher; Letizia Gaetana Lo Grasso; Francesco Giuliano
Original assignee: Sifi S.P.A.
Priority date: 2007-05-04
Filing date: 2008-05-02
Publication date: 2008-11-13
Also published as: ITMI20070890A1; WO2008136034A3

Abstract

The present invention relates to the use of ophthalmic pharmaceutical compositions for the treatment of glaucoma and ocular hypertension. Particularly, the invention relates to ophthalmic formulations comprising a new active ingredient, optionally in combination with other active ingredients typically used in the treatment of ocular hypertension or glaucoma.

Description

"OPHTHALMIC COMPOSITIONS FOR THE TREATMENT OF OCULAR HYPERTENSION AND GLAUCOMA"

FIELD OF THE INVENTION [OOOl] . The present invention relates to the use of ophthalmic pharmaceutical compositions for the treatment of glaucoma and ocular hypertension. Particularly, the invention relates to ophthalmic formulations comprising a new active ingredient, optionally in combination, with other active ingredients typically used in the treatment of ocular hypertension or glaucoma such as, for example: prostaglandins (latanoprost, travoprost, bimatoprost) , parasympathomimetics (pilocarpine) , α2-agonists

(apraclonidine, brimonidine) , carbonic anhydrase inhibitors - CAI - (brinzolamide, dorzolamide) or derivatives thereof. BACKGROUND OF THE INVENTION

[0-002] . Glaucoma is an optic neuropathy characterized by a progressive visual field reduction which can lead to blindness.

[0003] . This disease is generally associated to a pathological increase in intraocular pressure (IOP) , although there are some forms of glaucoma in which the IOP keeps within standard limits (12-20 mm Hg) . [0004] . The most common condition of this disease is represented by open angle glaucoma (chronic simple glaucoma, or wide-angle glaucoma) , in which the IOP increases due to a reduced aqueous humour outflow from the anterior" chamber. [0005] ♦ In the acute closed-angle glaucoma (primary closed-angle glaucoma, or closed-angle glaucoma) , the IOP increases, on the other hand, due to an obstruction of the aqueous humour flow in the anterior chamber, and this is a medical emergency. [0006] . Today, the ocular hypertone, although it is not longer considered a necessary element in glaucoma, is considered the primary risk factor for the development and progression of the glaucomatous ocular disease.

[0007] . Glaucoma has been treated so far with different types orf drugs (generally for topic ophthalmic use) , which act by reducing IOP through different mechanisms of action, some-times used in combination or concomitant therapy: β-blσckers, prostaglandins, carbonic anhydrase inhibitors (CAI), parasympathomimetics, etc. [0008] . Particularly, β-blockers act by blocking β- repectors at the level of the ciliary body, and by reducing the aqueous humour production, therefore IOP. [00093. A minimum action of β-blockers on the increase of aqueous humour outflow at the trabeculum has also been noted, which would determine. an IOP reduction. 1.0OlG]_* Therefore, several β-blockers are being used in tϊie clinical treatment of glaucoma, just since they lower LO-P.

[00111. β-blockers are first-choice drugs for the treatment of^" glaucoma (Gazzetta Ufficiale della Repubblica Italiana, March 14, 2007, p. 59-60, note 78). [00123. However, non-selective β-blockers for βl- receptors can cause serious undesired side-effects by systemic absorption, also after topic administration on the eye, such as to make them contraindicated, for example, in those subjects affected by bronchial asthma, in which the §2-receptors block may cause bronchial spasm. [00133. β-blockers are generally administered twice per day, although some particular formulations can allow only one administration per day, while maintaining their Pharmacolog-ical effect . SUMMSHY OF THE INVEMTQN-

[001.43. Therefore, the technical problem underlying the present invention is "to found an active ingredient belonging to the β-blockers family, which is free from the above-mentioned undesired side-effect, while being efficacious in lowering IOP.

[0015] . Such problem is solved by the use of ophthalmic pharmaceutical compositions as cited in the annexed main claim. rojQlδ] . Therefore, object of the invention is to provide an ophthalmic pharmaceutical composition useful in lowering IOP and in. the treatment of glaucoma . BRIEF DESCRIPTION OF THS DRAWINGS to017] . Further characteristics and the advantages of the present invention will be more clearly understood from the following description of. some embodiments, given by way of non-limiting example, with reference to the Figures, in whicfcu - Fig. 1 shows the chemical formula of the active ingredient according to the invention;

Fig. 2 shows a graph in which the effect of the active ingredient (1%) in lowering IOP in the normotensive New Zealand albino rabbit is compared to the control; - Fig. 3 shows a graph in which the effect of 2% carteolol in lowering IOF in the ncrmotensive New Zealand albino rabbit is compared to the cøntrol.

Fig. 4 shows—a_ graph in which the effect of G -5-% nebivσlol in lowering XOP in the normotensive New Zealand albino rabbit is compared to the effect of 0.5% timolol.

Fig. 5 shows a. graph in which the effect of 1% nebivolol in lowering IOP is compared to the control in a model of induced acute ocular hypertone in the rabbit by water-loading- DETAILED DESCRIPTION OF THE INVENTION [0018] . Following several studies and experiments, it has been surprisingly observed that ophthalmic compositions comprising neMvαϊol, {RSSS + SRRR)-OC^a'- iminodiinethylene-bis-[6-fluoro-2-chromanmethanol]. , as an active ingredient, both as a raceme mixture and in the individual d and 2 enantiozners thereof, again, both as a base and a derivative, (salt or ester₇ particularly methyl, ethyl or propyl ester) , exert an IOP lowering effect at 1% concentration in the normotensive rabbit by an extent which is comparable to the one exerted by 2% carteolol (Figs. 2 and 3) . In the same experimental model, the 0.5% nebivolol proved to be as efficient as 0.5% timolol in producing a significative ocular tone decrease (Fig.4) . Similarly, studies carried out on a model of acute ocular hypertension in the rabbit, have shown that 1% neb-ivcrlol is -able tcr induce a significative reduction of IOP increase following water-loading (Fig.5) . Furthermore, studies carried -out_ in the jrs.tr have shown that nebivαlol is- able to signifieatively reduce IOP in a model of clironic ocular hypertension.

[0019] . Contextually, the present invention also refers to the optional use of nebivolol in combination with other molecules possibly used for the treatment of glaucoma, such as, for example: α-antagonists, potassium channel inhibitors, cannabinoids . [0020]. Nebivolol is a. third generation . ^-antagonist agent which is highly selective for ^"βl-receptors, lacking a sympathomimetic action, currently registered - in the pharmaceutical form of an oral tablet - in -Several Countries of the European Community for the treatment of arterial hypertension. This β-blocker is further able to induce also a vasodilatation effect through a eNOS

(endothelial NO synthetase) -mediated mechanism at the vessel endothelium. [0021] . Some patents (EP 0801564, Janssen JEharmaceutiσa N.V.) also claim an antioxidant action for nebivolol, determined by the presence of hydroxyls - OH - within the structure thereof, which would act as oxygen radical scavengers, similarly to SOD {superoxide dismutase) . t0022] _^ Of the 2 enantiomers of nebivolol, d -eπantiomer is approximately 100 times stronger than 2 enantiomer in the βl-blocking action thereof,.- while the tsrø isomers are- equivalent as regards their a-ctivity on eN©S-, -determining an ON release from the vessel -endothelium, with a vasodilatation effect by reducing vessel "resistances.

[0023] . Both the racemic form and the d enantiomer of nebivolol are characterized by a high affinity for βl- receptors, and a low affinity for β2-receptors. This makes the active ingredient safer, since it is less likely to cause undesired systemic side-effects, for example, circulatory, respiratory, and metabolic effects (Joexn B^, Soltau e Thorn J.Zimmermann., Survey of Ophthalmology, ^'L₁. S.I, 2002, Changing Paradigms in the Medical Treatment of Glaucoma) . [0024] . Nebivolol, among the possible derivations of which the most used for pharmaceutical preparations is the hydrochloride form, is, also in this form, a highly water- insoluble active ingredient. [0025] . Patent EP 0801564 (Janssen Pharmaceutica N.V..) disclosed the use of special excipients or complexes with β-cyclodextrins to attempt to improve solubility and/or bioavailability of nebivolol, particularly, again by systemic administration (oral, intramuscular, intravenous or subcutaneous, rectal, intranasal) or topic (buccal or dermal) .

[0026] . In another patent (EP Q744946, Janssen Pharmaceutica- N.V. ), the active ingredient bioavailability is optimized by the use of micronized nebivolol_t again f-or oral use (tablets) . [0027] . Anyhow, no one of the patents discloses or suggests the use of nebivolol for lowering IOP or as an antiglaucomatous medication, not its ophthalmic use. [0028] . The ophthalmic compositions of the invention comprise 0.01-1.5%, preferably 0.05-1.2%, even more preferably 0.1-1% nebivolol. [0029] . The low affinity of nebivolol to the 32- receptors makes it a safer active ingredient in the event of a systemic absorption, as already noticed, for example, for betaxolol. [003O]. Advantageously, the active ingredient has been formulated in a oil-in-water emulsion, which has already been the object, as a vehicle, of the patent applications PCT/IT2007/000239 and PCT/EP2007/064530 , incorporated herein in their entirety as a reference, in which the presence of the inner oil phase and phospholipids allowed formulating nebivolol in a useful and novel manner for ocular topic administration. In brief, said patent applications covers a phospholipidic component which is composed by naturally occurring amphoionic phospholipids, and an oil component composed by naturally occurring oils emulsioned in water. The ratio of the oil and phospholipidic components may be from A:1 to 1:1, preferably, it is 3:1, even more preferably the ratio, xs about 2.3:1. [0031], As a non-limiting example, other topic pharmaceutical forms plausible for a highly water- insoluble active ingredient such as nebivolol or derivatives thereof can be considered: ointment, solid inserts, suspensions, gels, oily solutions, thickened solutions, solutions achieved by means of cyclodextrins, liposomes, nanoparticles, micelles- for topic ocular application or intraocular injection.

[0032] . Non-limiting examples of such formulations are reported in Tables 1-3. TABLE 1. Nebivolol - emulsion

EXAMPLE

{00333. In order to test the efficacy of nebivolol on IOP lowering, the following in-vivo models have been used: normotensive rabbit; induced acute ocular hypertone in the same species; and a model of chronic ocular hypertension in the rat .

[0034] . The experiments on the normotensive rabbit served to compare the effect on IOP of the 1% nebivolol emulsion to that of a 2% carteolol solution. How it will be appreciated in the experimental part, the two products prove to be equally efficient in producing a significant

IOP lowering in the experimental model which has been used.

[0035] . Similarly, in the same experimental model, comparable IOP lowering curves have been obtained for the 0.5% nebivolol emulsion and for a 0.5% timolol aqueous solution. Furthermore_r the efficacy of nebivolol has been tested in two ocular hypertone experimental models-: an acute one in the rabbit, and a chronic one in the rat. In both models, nebivolol proved to be efficient in significantly reducing the experimentally induced ocular hypertone . Tolerability [0036] . The formulations having the composition reported in the description of the object of the present invention turn out to be well ophthalmically tolerated in the rabbit (Draize test) .

Efficacy of nebivolol in lowering IQP in normotensive New- Zealand albino rabbit [0037] . 12 normotensive New Zealand albino rabbits having an average weight of 2-3 kg have been subjected to acclimatation (6 days) , randomized, and divided into 2 groups of 6 animals each.

[0038] . The animals of the treatment group (1% nebivolol emulsion) have been treated with 100 μl 1% nebivolol in emulsion in their right eye, and 100 μl of the relative vehicle in their left eye. The animals of the control group have been treated with 100 μl of the same vehicle in both eyes. The IOP has been measured with an applanation tonometer <TonoPen Vet^®, Medtronics Ophthalmics,

Jacksonville, FL, USA) 30 mins before the treatment

{baseline) , then 30, 60, 120, 180, 240, and 360 mins after the administration.

[0039] . Subsequently, the variations of the IOP values which had been measured in the control and treated groups have been subjected to Two-way ANOVA statistical analysis and Bonferroni post-test, and plotted using Prism GraphPad™ (Fig. 2) . [0040] . The obtained data have been compared to those obtained in a similar experiment (n=9) , in which normαtensive New Zealand albino rabbits have been treated with 100 μl of a 2% carteolol solution to the relative vehicle used as a control (Fig. 3) , administered as previously indicated. The statistical analysis has been run according- to Two-way ANOVA and Bonferroni post-test, and the variations of the IOP values have been plotted using Prism GraphPad™.

[0041] . In- a similar experiment, the effects of topically administered 0.5% nebivolol and 0.5% timolol compared to a control group (n=5 animals each group) have been a&sessed. The results show that the two assessed products cause an IOP lowering in the normotensive rabbit by a comparable extent .

[0042] . The statistical analysis has been run according. to One--way ANOVA and Dunnett post-test, and the variations of the IOP values have been plotted using Prism GraphPad™

(Pig.4).

Results

[0043]. As it can be inferred from Figs. 2 and 3, the treatment with 1% nebivolol causes an IOP lowering in the treated eye with a Delta comparable to or higher than the one obtained with 2% carteolol.

[0044] . Similarly, it can be deduced from Fig. 4 that the treatment with 0.5% nebivolol produces an IOP lowering in the treated eye comparable to the one which is induced by Q~-5:%. timolol. Conclusion-s-

E-©=G45ϊ. It can be inferred from the experimental data

-±hat the nebivσlol performs an action on IOP in the normotensive animals whicϊi is comparable to the one which is obtained with carteolol or timolol, non-selective β~ folockers- commonly used in the clinical practice for the treatment of glaucoma.

Efficacy of nebivolol in lowering IQP in the model of induced acute ocular hypertone in the rabbit by water- loading.

[0046] . New Zealand albino male rabbits, weighing about 3-4 kg, have been subjected to acclimatation (6 days) , randomized,, and divided into 2 experimental groups. The animals of the treatment group have been treated with 100 μl 1% nebiv-Q-Lol in- emulsion in the left eye conjunctival sac- The animals of the control group have been treated -with l=Θ0 μ3_-vehicTe. ^"The., treatments have been carried out 30 -minutes¹ before water-loading. Ocular hypertension has been obtained by infusion of a 5% glucose solution (15 mL/kg body weight) through- the marginal ear vein in the nonanesthetized^" animal. The IOP has been measured with an applanation tonometer (TonoPen Vet^®, Medtronics Ophthalmias, Jacksonville, FL, USA) just before water- loading (T=O), then at 5, 10, 15, 20, 30, 40, 50, and 60 mins. after water-Loading.

[00473. The variations of IOP values which had been measured in the- control group and in the treated group have- been -sufoseguently subjected to statistical analysis Two-way MsøyΑ and. Bonferroni post-test and plotted using Prism GraphPad™ C?ig. 5) - Results

[0048] . How it can be inferred from Fig. 5, the treatment with 1% nebivolol determines a significant lowering of the IOP increase compared to the control group . Conclusions

It can be inferred from the experimental data that nebivolol is efficient in inhibiting the experimentally induced acute ocular hypertone in the albino rabbit.

.Efficacy of nebivolol in. a model of glaucoma in the rat Sprague-Dawley male- rats (250-300 g). have been, kept in standard,-cage, conditions, randomized, and- divided into tsaα treatment groupsτ nebivoloi emulsion, -and vehicle. Before the surgical procedure to induce chronic ocular -hypertension, the animals have been anesthetized with chloral hydrate (4OO mg/kg) intraperitoneally administered. The corneal analgesia has been further ensured by topic application of oxybuprocaine . Then, three episcleral veins have been exposed and cauterized. The IS animals intraocular pressure Eras been periodically monitored by using a digital tonometer. The assessment of the ocular hypotensive action, of nebivσlσl has been carried out at different periods of time from the drug administration in rats with- chronic- ocular hypertension and compared to the vehicle aσt±on. Results

The experimental data confirm that nebivolol is efficient in lowering chronic ocular hypertone induced by episcleral vein cauterization in the rat. Conclusions

Nebivolol turns out to be efficient also in reducing the ocular tone in a model of experimental glaucoma>

Claims

1. Use of nebivαiσl, or a salt thereof, or^" an ester thereof, selected from methyl, ethyl, ox -propyl ester, for the production of a medicament, for lowering ocular hypertension.

2. Use of nebivolol, or a salt thereof, or an ester thereof, selected from methyl, ethyl, or propyl -ester_r for the production of a medicament for the treatment of glaucoma.

3. The use of nebivolol according to the claims 1 or 2, in racemic form or optically active form..

4. The use of nebivolol according to any one of the claims 1-3 in compositions which are suitable for ocular administration.

5. The use according to claim 4_r in which such compositions are in the form xrE emulsions, ointments-, solid inserts, suspensions, gels-, oily solutions, thickened solutions, solutions obtained by_^ -means of cyclodextrins, liposomes, nanoparticles^", iπxcBlles-.

6. The use of compositions according to the claims 4 and 5 comprising 0.01-1.5%, preferably 0.05-1 -.2%. even more preferably 0.1-1% nebivolol.

7. Ophthalmic pharmaceutical compositions comprising nebivolol for use as an ocular medicament- 8. The compositions according to claim 6 for ocular topic

IT applications or intraocular injection.

9. The compositions according to claims 7 or- 8, comprising: 0.01-1.5%, preferably 0.05-1.2%, even more preferably 0.1-1% nebivolol, and a pharmaceutically-acceptable vehicle .

10. The pharmaceutical compositions according to claim 7, 8, or 9, in combination with 0.05-5% prostaglandins.

11. The pharmaceutical compositions according to claim 10, wherein said prostaglandins are selected from: latanoprost, travoprost, bimatoprost, or derivatives thereof .

12. The pharmaceutical compositions according to claim 7, 8, or 9, in combination with 0.05-5% parasympathomimetics .

13. The pharmaceutical compositions according to -claim 12, wherein the parasympathomimetic is pilocarpine or a derivative thereof.

14. The pharmaceutical compositions- according- to claim 7 , 8, or 9, in combination with 0.05-5% α2-agonists.

15. The pharmaceutical compositions according to claim

14, wherein said α2-agonist agentr is selected from apraclonidine, brimonidine, or derivatives thereof.

16. The pharmaceutical compositions according to claim 7,

8, or 9, in combination with 0.05-5% carbonic anhydrase inhibitors - CAI -.

17. The pharmaceutical compositions according to claim 16, wherein said carbonic anhydrase inhibitor is selected from brinzolamide, dorzolamide, or derivatives thereof .

18. The pharmaceutical compositions according to claim 7, 8, or 9, in combination with α-antagonists.

19. The pharmaceutical compositions according to claim 7, 8, or 9, in combination with potassium channel blockers.

20. The pharmaceutical compositions according to claim 7, 8, or 9, in combination with cannabinoids .