HK1241269B - Combinations of prostaglandins and nitric oxide donors - Google Patents

Description

Combination products of prostaglandins and nitric oxide donors

Technical Field

The present invention relates to compositions comprising a nitric oxide-releasing isomannide derivative and a prostaglandin _F2α analog. More particularly, the present invention discloses compositions for reducing intraocular pressure associated with glaucoma or other ocular diseases.

Background Art

Glaucoma, including hypertensive and normotensive glaucoma, is an eye disease characterized by progressive loss of visual field caused by irreversible damage to the optic nerve. If not properly treated, glaucoma may lead to blindness or significant loss of vision.

Prior art glaucoma treatments involve lowering intraocular pressure by administering drugs that reduce aqueous humor production or increase fluid drainage within the eye, such as beta-adrenergic blockers, alpha-agonists, cholinergics, carbonic anhydrase inhibitors, and prostaglandin analogs.

Among these drugs, prostaglandin analogs help to outflow aqueous humor from the sclera, thereby reducing intraocular pressure, and are therefore commonly used to treat glaucoma. However, in therapeutically effective amounts, prostaglandin analogs (e.g., bimatoprost, latanoprost, travoprost, tafluprost, and unoprostone isopropyl) may produce ocular side effects, such as eye irritation, conjunctival hyperkalemia, iritis, uveitis, macular edema, and increased iris pigmentation (Martindale, 33rd edition, page 1445).

In the treatment of glaucoma and ocular hypertension, drugs that have the effect of reducing intraocular pressure can be used in combination to enhance the intraocular pressure-lowering effect. For example, EP 0 286 903 discloses the use of a combination of prostaglandins and beta-adrenergic blockers, and US 2013/0116254 discloses the combined use of the intraocular blood pressure-lowering drugs bimatoprost, brimonidine, and timolol.

In addition, WO 2013/060673, WO 2014/170264 and WO 2014/063923 disclose the use of quinone nitric oxide donors alone and in combination with prostaglandin analogs for the treatment of glaucoma and intraocular pressure. The quinone nitric oxide donors are disclosed for ophthalmic use. However, the patent applications do not provide evidence of the effects of the combined use of quinone nitric oxide donors and prostaglandin analogs.

EP 2 238 143B discloses nitric oxide-releasing isohexylene (isohexide) derivatives. These compounds have been disclosed for the treatment of cardiovascular disease, hypertension, inflammation, pain, respiratory diseases, vascular diseases, nephropathy and other pathological diseases, including glaucoma and ocular hypertension. However, the patent does not provide evidence about the effect of the combination of nitric oxide-releasing isohexylene derivatives and prostaglandin analogs.

US 7,816,399 discloses the use of a mixture of latanoprost and a nitric oxide (NO) donor for the treatment or prevention of ocular hypertension or glaucoma.

The patent discloses that the combination of latanoprost and niprolol or sodium nitroprusside has an increased ocular tension-reducing effect compared to each compound used alone.

Summary of the Invention

The inventors have surprisingly discovered that the combined administration of a nitric oxide-releasing isomannide derivative and a prostaglandin _F2α analogue produces a greater degree of reduction in intraocular pressure and a longer duration of reduction in intraocular pressure than the same dose of either compound administered alone.

The synergistic intraocular pressure-lowering effect of the nitric oxide-releasing isomannide derivative and the prostaglandin _F2α analogue following co-administration allows for a reduction in the dose of the prostaglandin _F2α analogue, thereby reducing or eliminating the side effects typically associated with topical prostaglandin analogues.

Therefore, these combinations are useful as therapeutic agents for treating glaucoma and ocular hypertension by lowering intraocular pressure.

Thus, the present invention provides an effective ophthalmic composition for treating and/or preventing glaucoma and ocular hypertension with reduced side effects, thereby improving patient compliance.

The present invention relates to a composition comprising:

(i) a nitric oxide-releasing isomannide derivative of the following formula (I) or a stereoisomer thereof:

in:

X is -CO- or -COO-;

Y is

- a straight or branched C ₁ -C ₁₀ alkyl chain substituted by 1 or 2 -ONO ₂ groups, or

-C ₁ -C ₆ alkyleneoxy-C ₁ -C ₅ alkyl, wherein the alkyl group is substituted by 1 or 2 -ONO ₂ groups.

(ii) The prostaglandin F _2α analogue is selected from latanoprost, bimatoprost, travoprost, tafluprost or unoprostone isopropyl ester, and the preferred prostaglandin F _2α analogue is travoprost or bimatoprost.

A preferred embodiment of the present invention provides a composition comprising:

(i) a nitric oxide-releasing isomannide derivative of formula (I) selected from the group consisting of:

-(3R,3aR,6R,6aR)-6-Hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-(nitrooxy)butyrate (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-di(nitrooxy)hexanoate (Compound (3))

-(3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 3-(2,3-bis(nitrooxy)propoxy)propionate (Compound (4))

-(3R,3aR,6R,6aR)-6-Hydroxyhexahydrofuro[3,2-b]furan-3-yl 4,5-di(nitrooxy)hexanoate (Compound (5))

-(3R,3aR,6R,6aR)-6-Hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-(nitrooxy)butyl carbonate (Compound (6))

-4,5-Di(nitrooxy)hexyl(3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl carbonate (Compound (7))

-5,6-Di(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-di(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-di(nitrooxy)hexanoate (Compound (12))

and its stereoisomers,

(ii) The prostaglandin _F2α analogue is selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost and unoprostone isopropyl ester.

Another embodiment of the present invention provides a composition comprising:

(i) a nitric oxide-releasing isomannide derivative of formula (I) selected from the group consisting of:

-(3R,3aR,6R,6aR)-6-Hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-(nitrooxy)butyrate (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-di(nitrooxy)hexanoate (Compound (3))

-(3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 3-(2,3-bis(nitrooxy)propoxy)propionate (Compound (4))

-(3R,3aR,6R,6aR)-6-Hydroxyhexahydrofuro[3,2-b]furan-3-yl 4,5-di(nitrooxy)hexanoate (Compound (5))

-(3R,3aR,6R,6aR)-6-Hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-(nitrooxy)butyl carbonate (Compound (6))

-4,5-Di(nitrooxy)hexyl(3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl carbonate (Compound (7))

-5,6-Di(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-di(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-di(nitrooxy)hexanoate (Compound (12))

and its stereoisomers

(ii) Prostaglandin F _2α analogues, such as travoprost or bimatoprost.

Another embodiment of the present invention provides a composition comprising:

(i) a nitric oxide-releasing isomannide derivative of formula (I)

-(S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)-5,6-di(nitrooxy)hexanoate (Compound (12))

and

(ii) a prostaglandin _F2α analogue selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost and unoprostone isopropyl ester.

Another embodiment of the present invention provides a composition comprising:

(i) a nitric oxide-releasing isomannide derivative of formula (I)

-(S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)-5,6-di(nitrooxy)hexanoate (Compound (12))

and

(ii) Prostaglandin F _2α analogue, travoprost.

Another embodiment of the present invention provides a composition comprising:

(i) a nitric oxide-releasing isomannide derivative of formula (I)

-(S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)-5,6-di(nitrooxy)hexanoate (Compound (12))

and

(ii) Prostaglandin F _2α analogue, which is bimatoprost.

The weight ratio of the nitric oxide-releasing isomannide derivative of formula (I) to the prostaglandin F _2α analogue is generally 1:1-10000:1, preferably 5:1-1000:1.

The present invention also provides a composition comprising a nitric oxide-releasing isomannide derivative of formula (I) as defined above and a prostaglandin _F2α analogue for use in treating glaucoma, ocular hypertension and for reducing intraocular pressure associated with ocular diseases.

Another embodiment of the present invention provides an ophthalmic pharmaceutical formulation comprising at least one nitric oxide-releasing isomannide derivative of formula (I) as defined above, a prostaglandin _F2α analogue and at least one ophthalmically acceptable excipient.

Ophthalmic excipients may include, for example, buffers, tonicity agents, chelating agents, viscosity enhancers, solubilizers, surfactants, antioxidants, preservatives, or ophthalmically acceptable carriers.

The ophthalmic pharmaceutical preparations of the present invention may be in the form of solutions, suspensions, emulsions, dispersions, topical eye drops or tear gels.

Typically, the ophthalmic pharmaceutical formulations of the present invention include the compound of formula (I) in an amount of about 0.001 to about 10 weight percent (w/v%) and the prostaglandin _F2α analog in an amount of about 0.0001 to about 0.2 w/v%.

The nitric oxide-releasing isomannide derivative of formula (I) is preferably used in an amount of about 0.005 to about 2.0 w/v%, and particularly preferably used in an amount of about 0.01 to about 0.5 w/v%. The prostaglandin _F2α analog is preferably used in an amount between about 0.0001 and about 0.1 w/v%, depending on the potency of the prostaglandin.

The combination of the nitric oxide-releasing isomannide derivative of formula (I) and the prostaglandin _F2α analogue of the present invention can be prepared as a dosage form, which contains effective amounts of each compound mixed in an appropriate mixing ratio; or used as a kit, each administration containing an effective amount of each compound, administered simultaneously or separately at certain intervals.

Nitric oxide-releasing isomannide derivatives of formula (I) are described in EP 2 238 143 B; this patent discloses the structure, preparation and physical properties of these compounds.

The prostaglandin _F2α analogs used in the composition of the present invention are known as drugs for treating glaucoma and are:

Latanoprost is 5-heptenoic acid, 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-,1-methylethyl ester, (5Z)-;

Bimatoprost is 5-heptenamide, 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-penten-1-yl]cyclopentyl]-N-ethyl-,(5Z)-;

Travoprost is 5-heptenoic acid, 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-yl]cyclopentyl]-,1-methylethyl ester, (5Z)-;

Tafluprost is 5-heptenoic acid, 7-[(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxy-1-buten-1-yl]-3,5-dihydroxycyclopentyl]-,1-methylethyl ester, (5Z)-;

Unoprostone isopropyl ester is 5-heptenoic acid, 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-(3-oxodecanyl)cyclopentyl]-, 1-methylethyl ester, (5Z)-.

Latanoprost, bimatoprost, travoprost, tafluprost or unoprostone isopropyl ester are all commercially available.

Specific implementation methods

Example

Example 1

Intraocular pressure (IOP)-lowering activity in normotensive New Zealand White (NZW) rabbits

The intraocular pressure (IOP) lowering activity of a combination of compound (12) (0.1%) and travoprost (0.004%) was evaluated in normotensive rabbits.

Adult male NZW rabbits weighing 1.8-2.0 kg were used in the experiments.

IOP was measured using a tonometer 30 CLASSIC ^™ before topical application (basal) and at different time points (30, 60, 120, 180, 240, and 300 minutes). Travoprost (0.004%) or vehicle (5% Crempphor-EL; 0.3% DMSO; 0.2 mg/ml BAC in PBS at pH 6.0) was administered topically 5 minutes before compound (12) (0.1%) or vehicle (same as described below) was applied as eye drops into the conjunctival pocket. Eyes were randomly assigned to different treatment groups. Before each group of intraocular pressure measurements, one drop of 0.4% buoxycaine hydrochloride (Novesine, Sandoz) was instilled in each eye.

Results As shown in the table, the intraocular pressure-lowering activity of the combination of compound (12) and travoprost is expressed as the change in IOP (30, 60, 120 and 300 minutes after topical administration) relative to vehicle and relative to basal IOP (mean ± SE).

The combination of compound (12) (0.1%) and travoprost (0.004%) resulted in increased IOP lowering activity compared to compound (12) (0.1%) or travoprost (0.004%) alone. In addition, the duration of action of the combination was prolonged compared to the administration of compound (12) (0.1%) or travoprost (0.004%) alone.

The above results indicate that the combined use of the nitric oxide-releasing isomannide derivative of formula (I) and the prostaglandin _F2α analogue can enhance the intraocular pressure lowering effect and increase the duration of the intraocular pressure lowering effect. The intraocular pressure lowering effect is greater than that of simple addition, and in particular, the duration is longer.

Example 2

Intraocular pressure (IOP) lowering activity in New Zealand White (NZW) rabbits with ocular hypertension

The intraocular pressure (IOP) lowering activity of a combination of compound (12) (0.3%) and travoprost (0.004%) was evaluated in ocular hypertensive rabbits.

Adult male NZW rabbits weighing 1.8-2.0 kg were used in the experiment.

0.1 ml of hypertonic saline (5%) was injected into the vitreous humor of both eyes of NZW rabbits. IOP was measured using Tono-Pen AVIA at different time points (30, 60, 120 and 240 minutes) after the hypertonic saline injection and before the topical drug administration (basal).

Travoprost (0.004%) or vehicle (5% Cremophor-EL; 0.3% DMSO; 0.2 mg/ml BAC in PBS, pH 6.0) was topically applied 15 minutes before hypertonic saline injection.

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

Immediately before each set of intraocular pressure measurements, one drop of 0.4% buoxycaine hydrochloride (Novesine, Sandoz) was instilled into each eye.

Table 2 shows the intraocular pressure-lowering effects of travoprost, compound (12), and the combination of compound (12) and travoprost (30, 60, 120, and 300 minutes after topical administration).

The results reported in Table 2 are expressed as changes in IOP relative to vehicle and relative to basal IOP (30, 60, 120 and 300 minutes after topical administration) (mean ± SE).

The results showed that the combination of compound (12) and travoprost could increase the IOP lowering activity compared with compound (12) or travoprostone administered alone, and the combination of compound (12) and travoprost could induce enhanced and sustained IOP lowering effect over a longer time point.

Claims (10)

1. A composition comprising: (i) Nitric oxide release isomannitol derivative (S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl)-5,6-bis(nitrooxy)hexanoate; (ii) A prostaglandin F _2α analogue selected from latanoprost, bimatoprost, travoprost, tafluprost, or unoprostone isopropyl ester. 2. The composition of claim 1, wherein the prostaglandin _F2α analog is travoprost. 3. The composition of claim 1, wherein the prostaglandin _F2α analog is bimatoprost. 4. The composition of any one of claims 1-3, wherein the weight ratio of nitric oxide-releasing isomannitol derivative (S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl)-5,6-bis(nitrooxy)hexanoate to prostaglandin _F2α analog is 1:1 to 10000:1. 5. The composition of any one of claims 1-3, wherein the weight ratio of the nitric oxide-releasing isomannitol derivative (S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl)-5,6-bis(nitrooxy)hexanoate to the prostaglandin _F2α analog is 5:1 to 1000:1. 6. The composition of any one of claims 1-3, used as a medicine. 7. The composition of any one of claims 1-3, for treating glaucoma and ocular hypertension. 8. The composition of any one of claims 1-3 for reducing intraocular pressure associated with eye diseases. 9. An ophthalmic pharmaceutical preparation comprising the composition of any one of claims 1-4 and at least one ophthalmic excipient. 10. A kit comprising: a nitric oxide-releasing isomannitol derivative (S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl)-5,6-bis(nitrooxy)hexanoate and a prostaglandin _F2α analog selected from latanoprost, bimatoprost, travoprost, tafluprost, or unoprostone isopropyl ester, the kit being used to administer the compound simultaneously or at time intervals.