GB2432526A

GB2432526A - Use of ifenprodil for the treatment of ophthalmic diseases

Info

Publication number: GB2432526A
Application number: GB0523961A
Authority: GB
Inventors: Andrew Douglas Baxter
Original assignee: Arakis Ltd
Current assignee: Sosei R&D Ltd
Priority date: 2005-11-24
Filing date: 2005-11-24
Publication date: 2007-05-30
Also published as: GB0523961D0

Abstract

Ifenprodil has been found to be useful in the treatment of ophthalmic disease states characterized by ocular inflammation, dry eye disorders, increased ocular pressure, pathologic ocular angiogenesis and retinal or sub-retinal edema. Examples of such diseases include age-related macular degeneration, diabetic retinopathy, choroidal neovascular membrane, cystoid macular edema, epi-retinal membrane, macular hole, dry eye, uveitis or glaucoma.

Description

1 2432526 The Treatment of Ophthalmic Diseases

Field of the Invention

This invention relates to the use of Ifenprodil and isomers and metabolites of Ifenprodil for the treatment of ophthalmic diseases characterized by ocular inflammation, dry eye disorders, increased intra-ocular pressure, pathologic ocular angiogenesis and/or retina or sub-retinal edema.

Background

Diseases and degenerative conditions of the optic nerve and retina are the leading causes of blindness in the world. A significant degenerative condition of the retina is age-related macular degeneration (ARMD). ARMD is the most common cause of blindness in people over 50 in the USA and its prevalence increases with age. ARMD is classified as either wet (neovascular) or dry (non-neovascular) where the dry form of the disease is the most common. Macular degeneration occurs when the central retina has become distorted and thinned usually associated with age but also charactensed by intra-ocular inflammation and angiogenesis (wet ARMD only) and/or intra-ocular infection.

Retinopathy associated with diabetes is a leading cause of blindness in type I diabetes, and is also common in type II diabetes. The degree of retinopathy depends on the duration of diabetes, and generally begins to occur ten or more years after onset of diabetes. Diabetic retinopathy may be classified as non-proliferative, where the retinopathy is charactensed by increased capillary permeability, edema and exudates, or proliferative, where the retinopathy is characterised by neovasculansation extending from the retina to the vitreous, scarring, deposit of fibrous tissue and the potential for retinal detachment. Diabetic retinopathy is believed to be caused by the development of glycosylated proteins due to high blood glucose. The subsequent generation of free-radicals resulting in oxidative tissue damage, local inflammation and production of growth factors (such as VEGF and FGF) and inflammatory mediators leads to inappropriate neovasculansation in common with the wet form of ARMD. Several other less common retinopathies include choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi-retinal membrane (ERM) and macular hole. Today, no drugs approved for the treatment of diabetic retinopathy or macular edema. The current standard treatment is laser photocoagulation which by destroying local tissue, deceases the production of cytokines and growth factors but is unfortunately cytodestructive and causes permanent impairment of vision. These neovasular diseases have the potential to be treated with angiostatic agents in combination with anti-inflammatory drugs.

Dry eye, or keratoconjunctivitis, is a common ophthalmological disease affecting millions of Americans eath year. The condition is particularly prevalent in post-menopausal women due to hormonal changes caused by the cessation of fertility. Dry eye is primarily caused by the break-down of the pre-ocular tear film which results in dehydration of the exposed outer surface. There is a strong rationale that ocular inflammation as a result of pro-inflammatory cytokines and growth factors play a major role in the underlying causes of dry eye. As such locally administered anti-cytokine or general anti-inflammatory agents are often used in the treatment of dry eye.

Another disease of the interior of the eye is uveitis, or inflammation of the uveal tract. The uveal tract (uvea) is composed of the iris, ciliary body and choroid.

Uveitis may be caused by trauma, infection or surgery and can affect any age group.

The disease is classified anatomically as anterior, intermediate, posterior or diffuse.

Anterior uveitis affects the anterior portion of the eye including the iris. Intermediate uveitis, also called peripheral uveitis, is centred in the area immediately behind the iris and lens in the region of the ciliary body. Posterior uveitis may also constitute a form of retinitis, or it may affect the choroids and the optic nerve. Diffuse uveitis involves all parts of the eye. The most common treatment of uveitis is with locally administered glucocorticosteroids often in combination with other anti-inflammatory drugs. Although these drugs are effective in the treatment of many forms of ocular inflammation they have several side-effects including endophthalmitis, cataracts and elevated intra-ocular pressure (lOP). There is a need for potent anti-inflammatory agents with an improved side effect profile, the so-called non-steroid steroid, for the treatment of ophthalmic inflammation and edema.

Glaucoma is made up of a collection of eye diseases that cause vision loss by damage to the optic nerve. Elevated lOP due to inadequate ocular drainage is the primary cause of glaucoma. Glaucoma often develops as the eye ages, or it can occur as the result of an eye injury, inflammation, tumour or in advanced cases of cataract or diabetes. As discussed above it can also be caused by the increase in lOP caused by treatment with steroids. Drug therapies that are proven to be effective in glaucoma reduce lOP either by deceasing vitreous humor production or by facilitating ocular draining. Such agents are often vasodilators and as such act on the sympathetic nervous system and include adrenergic antagonists. There is a need for agents that can be delivered locally to the eye with minimal systemic side effects.

The use of ifenprodil (1) and isomers of ifenprodil for the treatment of general inflammatory conditions and pain is the subject of a separate application HOX1 Ifenprodil (1)

Summary of Invention

Surprisingly it has been found that ifenprodil (1), a drug used as a cerebral vasodilator and NMDA antagonist, is a potent anti-inflammatory agent. Furthermore, diastereoisomers of ifenprodil which have reduced primary activity against alpha-adrenoreceptors and the NMDA receptor retain this anti-inflammatory action.

Ifenprodil (1) suffers from extensive first pass metabolism which makes the compound ideal for topical delivery where systemic side effects can be minimised.

The unexpected profile of ifenprodil and its isomers is consistent with the non- steroid steroid and provides cytokine modulation with down regulation of pro-inflammatory cytokines (such as TNFa and IL-1f3) and growth factors involved in neovascularisation (such as FGF and VEGF) and upregulation of anti-inflammatory cytokines (such as IL-b) in combination with alpha-adrenoreceptor blocking activity resulting in vasodilation.

Description of the Invention

In this specification, reference to "treatment" includes any form of therapy, including curative and prophylactic.

Local administration of Ifenprodil (1), or an isomer of ifenprodil, or a metabolite of ifenprodil to the eye will allow the treatment of a range of ophthalmic diseases such as ARMD, retinopathies (including diabetic retinopathy), dry eye, uveitis and even glaucoma with minimal systemic side-effects.

It is understood that the invention refers to free-base, salts, e.g. the hydrochloride and hemi-tartarate, metabolites and pro-drugs thereof, as well as any diastereomers and enantiomers of (1).

According to another aspect of the invention, some of the isomers of formula (1) have vasodilator properties by antagonism at alpha adrenoceptors. These agents while being particularly interesting in the treatment of glaucoma represent the least preferred isomers for the treatment of ocular inflammatory diseases.

However, according to an additional aspect of the invention, the preferred diastereomer or enantiomer of (1) for the treatment of ARMD, retinopathies (including diabetic retinopathy), dry eye and uveitis has cytokine/growth factor modulatory activity but little or no activity at the alpha adrenoreceptors. This activity may be determined by use of the appropriate in vitro and in vivo assays.

The compounds of formula (1) may be used according to the invention when the patient is also administered or in combination with another therapeutic agent selected from angiostatic peptides, such as angiostatin; angiostatic steroids, such as anecortave acetate; modulators of VEGF or FGF, such as zactima; non-steroidal anti-inflammatory drugs (NSAID5) formulated for ocular use such as flurbiprofen, diclofenac and ketorolac; glucocorticosteroids, such as methylprednisolone; leukotriene modulators such as zilueton; anti-histamines such as cetinzine, loratidine, ketotifen and the like; and general cytokine/growth factor modulating agents such as cyclosporin A, diacerein, tetracyclines, fluoroquinolone antibiotics, quinoline antimalanals, statins, phosphodiesterase inhibitors and the like.

Compounds of formula (1) may also be administered before, during or after laser photocoagulation therapy.

The preferred route of administration is topical to the eye although other forms of application could include intraocular injection. An additional aspect of the invention describes formulations of compounds of general formula (1) suitable for topical application to the eye or intraocular injection. The dose of the active agent will depend on the nature and degree of the condition, the age and condition of the patient and other factors known to those skilled in the art. A typical dose is 0.01-mg given one to three times per day.

Claims

Claims 1. Use of ifenprodil for the treatment of an ophthalmic

condition.

2. Use according to claim 1, wherein the ophthalmic condition is age-related macular degeneration (ARMD).

3. Use according to claim 1, wherein the ophthalmic condition is diabetic retinopathy.

4. Use according to claim 1, wherein the ophthalmic condition is choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi-retinal membrane (ERM) or macular hole.

5. Use according to claim 1, wherein the ophthalmic condition is dry eye.

6. Use according to claim 1, wherein the ophthalmic condition is uveitis.

7. Use according to any preceding claim, wherein the compound is in the form of the enantiomer or diastereomer that has relatively little or no activity at the a adrenoceptor.

8. Use according to claim 1, wherein the ophthalmic condition is glaucoma.

9. Use according to claim 8, wherein the compound is in the form of the enantiomer or diastereomer that also has a adrenoceptor antagonist activity.

10. Use according to any preceding claim, wherein the compound is to be administered before, during or after laser photocoagulation therapy.

11. Use according to any preceding claim, wherein the compound is formulated for topical application to the eye or for intraocular injection.

12. Use according to any preceding claim, wherein the patient to be treated is also administered another therapeutic agent selected from angiostatic peptides, such as angiostatin; angiostatic steroids, such as anecortave acetate; modulators of VEGF or FGF, such as zactima; non-steroidal anti-inflammatory drugs (NSAIDs) formulated for ocular use such as flurbiprofen, diclofenac and ketorolac; glucocorticosteroids, such as methylprednisolone; leukotriene modulators such as zilueton; anti-histamines such as cetinzine, loratidine, ketotifen and the like; and general cytokine/growth factor modulating agents such as cyclosponn A, diacerein, tetracyclines, fluoroquinolone antibiotics, quinoline antimalanals, statins, phosphodiesterase inhibitors and the like.

13. Use according to claim 12 wherein compound (1) and said another agent are provided in combination.