COMBINATIONS OF PROSTAGLANDINS AND NITRIC OXIDE DONORS

Abstract

The present invention relates to compositions for treating glaucoma and elevated ocular pressure. The compositions comprise a nitric oxide releasing isomannide derivative and a prostaglandin F.sub.2α analog.

Claims

1. A composition comprising: (i) a nitric oxide releasing isomannide derivative of the following formula (I) or a stereoisomer thereof: ##STR00029## X is —CO— or —COO—; Y is straight or branched C.sub.1-C.sub.10 alkyl chain, substituted with one or two —ONO.sub.2; or C.sub.1-C.sub.6 alkylenoxy-C.sub.1-C.sub.5 alkyl wherein the alkyl group is substituted by one or two —ONO.sub.2 groups. (ii) a prostaglandin F2α analog selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost or unoprostone isopropyl.

2. A composition according to claim 1 wherein the prostaglandin F2α analog is travoprost or bimatoprost.

3. A composition according to claim 1 wherein (ii) the nitric oxide releasing isomannide derivative of formula (I) selected from the group: (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-(nitrooxy) butanoate (Compound (1)) (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 6-(nitrooxy)hexanoate (Compound (2)) (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 5,6-bis (nitrooxy) hexanoate (Compound (3)) (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 3-(2,3-bis(nitrooxy)propoxy)propanoate (Compound (4)) (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4,5-bis (nitrooxy)hexanoate (Compound (5)) (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-(nitrooxy) butyl carbonate (Compound (6)) 4,5-bis(nitrooxy)hexyl(3R,3aR,6R,6aR)-6-[3,2-b]furan-3-yl carbonate (Compound (7)) 5,6-bis(nitrooxy)hexyl(3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl carbonate (Compound (8)) 2-(2,3-bis(nitrooxy)propoxy)ethyl(3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl carbonate (Compound (9)) 3,3-dimethyl-5,6-bis(nitrooxy)hexyl (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl carbonate (Compound (10)) (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 6-(nitrooxy)hexyl carbonate (Compound (11)) (S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate (Compound (12)) and stereoisomer thereof.

4. A composition according to claim 1 wherein: (i) the nitric oxide releasing isomannide derivative of formula (I) is—(S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate (Compound (12)).

5. A composition according to claim 1 wherein: (ii) the nitric oxide releasing isomannide derivative of formula (I) is—(S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate (Compound (12)) (iii) the prostaglandin F2α analog is travoprost.

6. A composition according to claim 1 wherein: (i) the nitric oxide releasing isomannide derivative of formula (I) is—(S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate (Compound (12)) (ii) the prostaglandin F2α analog selected is bimatoprost.

7. The compositions according to claim 1 wherein the weight ratio of the nitric oxide releasing isomannide derivative of formula (I) to the prostaglandin F2α analog is 1:1 to 10000:1.

8. The compositions according to claim 7 wherein the weight ratio of the nitric oxide releasing isomannide derivative of formula (I) to the prostaglandin F2α analog is 5:1 to 1000:1.

9. The compositions according to claim 1 for use as medicament.

10. The compositions according to claim 1 for use in the treatment of glaucoma and ocular hypertension.

11. The compositions according to claim 1 for use in the reduction of intraocular pressure associated with ocular diseases.

12. Ophthalmic pharmaceutical formulations comprising a composition according to claim 1 and at least one ophthalmic excipient.

13. A kit comprising: a nitric oxide releasing isomannide derivative of formula (I) according to claim 1 and a prostaglandin F2α analog according to claim 1 for administering the compounds simultaneously or separately at an interval.

Description

EXAMPLES

Example 1

[0084] Intraocular Pressure (IOP) Lowering Activity in Ocular Normotensive New Zealand White (NZW) Rabbits

[0085] The Intraocular pressure (IOP) lowering activity of the combination of compound (12) (0.1%) and travoprost (0.004%) was assessed in ocular normotensive rabbits.

[0086] Adults male NZW rabbits weighting 1.8-2.0 Kg were used in the experiments.

[0087] IOP was measured using a pneumatonometer 30 CLASSIC™ before topical application (basal) and at different time points (30, 60, 120, 180, 240 and 300 min) thereafter. Travoprost (0.004%) or vehicle (5% cremophor-EL; 0.3% DMSO; 0.2 mg/ml BAC in PBS pH 6.0) were topically administered 5 minutes prior to compound (12) (0.1%) or vehicle (same as above) as eye drops into the conjunctiva pocket. Eyes were randomly assigned to different treatment groups. One drop of 0.4% oxybuprocaine hydrochloride (Novesine, Sandoz) was instilled in each eye immediately before each set of ocular pressure measurements.

[0088] Results are reported in the table in which the ocular hypotensive activity of the combination, of compound (12) and of travoprost are expressed as IOP change (at 30, 60, 120 and 300 minutes following topical administration) versus vehicle and versus IOP at basal (mean±standard error).

[0089] The combination of compound (12) (0.1%) and travoprost (0.004%) results in increased IOP lowering activity compared to either compound (12) (0.1%) or travoprost (0.004%) given alone. Moreover, the effects of the combination last significantly longer than either compound (12) (0.1%) alone or travoprost (0.004%) alone.

[0090] The above mentioned results revealed that an enhanced intraocular pressure lowering effect and improvement of the duration of intraocular pressure lowering action could be obtained by using a nitric oxide releasing isomannide derivative of formula (I) and a prostaglandin F.sub.2α analog in combination. The intraocular pressure lowering effect is greater than simple additivity, especially at the longer durations.

TABLE-US-00001 TABLE 1 Intraocular pressure (IOP) lowering activity in ocular normotensive NZW rabbits IOP change (mmHg) 30 60 120 180 300 minutes minutes minutes minutes minutes Compound −1.4 ± 0.6 −2.1 ± 0.4 −0.3 ± 0.3  0.1 ± 0.5  1.1 ± 0.8 (12) Travoprost −1.6 ± 1.6 −0.9 ± 1.0 −1.1 ± 1.2 −0.8 ± 0.4 −0.6 ± 0.1 Compound −3.9 ± 0.8 −2.6 ± 0.9 −3.2 ± 0.6 −3.4 ± 0.5 −2.6 ± 0.7 (12) + Travoprost

Example 2

[0091] Intraocular Pressure (IOP) Lowering Activity in Ocular Hypertensive New Zealand White (NZW) Rabbits

[0092] The Intraocular pressure (IOP) lowering activity of the combination of compound (12) (0.3%) and travoprost (0.004%) was assessed in ocular hypertensive rabbits.

[0093] Adult male NZW rabbits weighting 1.8-2.0 Kg were used in the experiments.

[0094] NZW rabbits were injected with 0.1 ml of hypertonic saline (5%) into the vitreous humor of both eyes. IOP was measured using a Tono-Pen AVIA Vet® at different time points (30, 60, 120 and 240 min) following hypertonic saline injection as well as before topical drug application (basal).

[0095] Travoprost (0.004%) or vehicle (5% cremophor-EL; 0.3% DMSO; 0.2 mg/ml BAC in PBS pH 6.0) were topically administered 15 min before hypertonic saline injection.

[0096] Compound (12) (0.3%) or vehicle (5% cremophor-EL; 0.3% DMSO; 0.2 mg/ml BAC in PBS pH 6.0) were topically administered immediately after hypertonic saline injection. Eyes were randomly assigned to different treatment groups.

[0097] One drop of 0.4% oxybuprocaine hydrochloride (Novesine, Sandoz) was instilled in each eye immediately before each set of ocular pressure measurements.

[0098] The ocular hypotensive effects (at 30, 60, 120 and 300 minutes following topical administration) of travoprost, compound (12) and the combination of compound (12) and travoprost are reported in table 2.

[0099] The results reported in table 2 are expressed as IOP change (at 30, 60, 120 and 300 minutes following topical administration) versus vehicle and versus IOP at basal (mean±standard error).

[0100] The results show that the combination of compound (12) and travoprost has an increased IOP lowering activity compared to either compound (12) or travoprost given alone and that the combination of compound (12) and travoprost induces an enhanced and sustained intraocular pressure lowering effect at longer time points.

TABLE-US-00002 TABLE 2 Intraocular pressure (IOP) lowering activity in ocular hypertensive NZW rabbits IOP change (mmHg) 30 60 120 240 minutes minutes minutes minutes Travoprost −2.4 ± 0.5 −5.0 ± 0.8 −5.1 ± 0.7 −1.7 ± 0.4 Compound (12) −2.4 ± 0.6 −7.7 ± 0.5 −6.4 ± 0.5 −1.8 ± 0.6 Compound (12) + −2.5 ± 0.8 −9.6 ± 1.0 −9.6 ± 0.8 −3.2 ± 0.7 travoprost