IT201900002441A1 - Compound useful for the treatment of glaucoma - Google Patents

Description

The present invention relates to a physiological supplement or medicament for the prevention or treatment of glaucoma. In particular, the present invention relates to mildronate, at a dose lower than 0.5%, for use for the prevention or treatment of open-angle glaucoma, in which mildronate is administered in the form of eye drops.

Field of the invention

Glaucoma is the second leading cause of blindness worldwide and can occur at different ages. Glaucoma is classified into congenital, open angle and closed angle, according to the underlying causes of the decrease in the outflow of aqueous humor. Each category is then divided into primary and secondary forms (Coleman A.L., Glaucoma, Lancet 1999; 354: 1803-10). The latter commonly occur during exfoliation syndrome, pigment dispersion syndrome, inflammation or neo vascularization.

The goal of glaucoma therapy is to prevent further vision loss and to avoid a negative impact on the patient's quality of life. Current therapies induce a reduction in ocular pressure such as to prevent further damage to the optic nerve. In fact, the progression of damage is determined by changes in the optic nerve or visual field that are consistent with the loss of multiple ganglion cells or axons.

The classes of drugs used in the treatment of glaucoma are:

-cholinergic agonists for topical use (eg pilocarpine, carbachol), which increase the outflow of aqueous humor; side effects consist of: increased bronchial secretion, nausea, vomiting, diarrhea, increased myopia, eye or eyebrow pain, decreased vision, apnea;

- beta-adrenergic antagonists for topical use (eg, timolol, carteolol, levobunolol, betaxolol), which reduce the production of aqueous humor; side effects consist of: congestive heart failure, bronchospasm, bradycardia, depression, confusion, impotence, worsening of myasthenia gravis, blood cholesterol increase;

-adrenergic agonists for topical use (eg, epinephrine, apraclonidine, brimonidine), which reduce both resistance to efflux and the production of aqueous humor; side effects consist of: increased blood pressure, tachyarrhythmias, tremors, anxiety, headache, pupil dilation, allergic reactions;

- carbonic anhydrase inhibitors for topical or oral use (eg, topical dorzolamide and brinzolamide; oral acetazolamide and metazolamide), which reduce the production of aqueous humor; side effects consist of: malaise, anorexia, depression, paraesthesia, abnormalities of serum electrolytes, kidney stones, blood dyscrasias, allergic reactions; taste changes (bitter or sour taste sensation);

- analogues of prostangladins (eg latanoprost), which increase the efflux of aqueous humor through the uveoscleral path; side effects consist of increased pigmentation of the iris, eyelashes, eyelid skin and hypertrichosis.

It can be understood from what has been said so far that current therapy is mainly, if not exclusively, aimed at controlling ocular pressure through an action on aqueous humor, both as regards its production and its efflux.

In glaucoma there is a progressive degeneration of ganglion cells, linked for some of them to the apoptotic event (N. Pescosolido and al. Acta Ophtalmologica Scandinavica, 1988, Supplement 227, 20-21). Cell death from apoptosis is also accompanied by necrosis, for which there is still no means to prevent it. Conversely, one can think of acting on the apoptotic phenomenon, effectively exercising a neuroprotection (McKinnon, 1997, Curr. Op. Ophthalmol. 8: 28-37). As for the glaucoma model based on the mechanism of apoptosis, see the aforementioned work by Pescosolido et al. and the Experimental Thesis of Specialization University of Rome “La Sapienza”, Institute of Ophthalmology, by Renata Rosa, Academic Year 2000-2001.

Known technique

European patent application EP2842557 describes the use of mildronate, intravitreal, for the prevention or treatment of open-angle glaucoma.

In GEORGIAN MEDICAL NEWS no. 131, February 2006 (2006-02), p.

37-40 describes the intravitreal use of mildronate for the prevention or treatment of glaucoma.

In Database WPI Week 199249, & SU 1 703 108 A1 7Jan 1992 (Method for treating acute disorders of blood circulation in the fibrous tunic of eyeball), the intrabulbar and subconjunctival use of mildronate is described for the treatment of circulatory disorders of the retina.

In Database WPI Week 201234, & RU 2 421 191 C1 20 June 2011 (Method of treating dystrophic diseases of cornea) the sub-conjunctival use of mildronate is described, for the treatment of dystrophic disorders of the eye.

In Database WPI Week 200626, & RU 2 270 025 C1, 20 Feb. 2006 (Method of treating diabetic retinopathy) the use of a complex composition including, among other things, mildronate, for the treatment of diabetic retinopathy is described.

To date, there is still a need for a drug or a medical device capable of reducing intraocular pressure, which is therefore useful in the prevention or treatment of glaucoma.

At the same time, the need is also felt to have a drug / medical device with reduced side effects.

Description of the figures

Figure 1 shows the graph relating to the variation in intraocular pressure, over time (hours) after administration of eye drops / eye drops comprising 0.1% mildronate vs eye drops based on sterile physiological solution, in two groups of rats. healthy (250 g Sprague Dawley male rats; 10 rats per group). This figure shows that the use of mildronate, one drop per eye both in the morning and in the evening, rapidly and statistically significantly reduces (p <0.01; Student's "t" test) intraocular pressure compared to administration. of physiological solution.

Figure 2 shows the graph relating to the variation of intraocular pressure, over time (hours) after administration of eye drops / eye drops comprising 0.5% mildronate vs eye drops based on sterile physiological solution, in two groups of rats. healthy (250 g Sprague Dawley male rats; 10 rats per group). This figure shows that the use of mildronate, one drop per eye both in the morning and in the evening, rapidly and significantly reduces intraocular pressure compared to the administration of physiological solution.

Description of the invention

It has now surprisingly been found that mildronate in the form of eye drops, at a dose of 0.1%, is useful for the prevention or treatment of open angle glaucoma.

Therefore, an object of the present invention is mildronate for use for the prevention or treatment of open-angle glaucoma, in which mildronate is administered in the form of eye drops and at a preferred dose of 0.01-0.5% is a dose of 0.025-0.25; particularly preferred is a dose of 0.1%.

A further object of the present invention is mildronate for use for the prevention or treatment of open angle glaucoma, in which mildronate is administered in the form of eye drops, and optionally one or more ophthalmologically acceptable diluents and / or excipients.

A further object of the present invention is mildronate, in the form of eye drops, for use for the prevention or treatment of glaucoma, in which said composition is administered by ophthalmic route in the form of eye drops, one drop per eye twice a day.

A further object of the present invention is mildronate, in the form of eye drops, for use for the prevention or treatment of glaucoma, in which said composition is administered by the ophthalmic route as a physiological supplement or medicament.

The doses and posology will be determined by the attending physician, according to his experience, the state of the pathology and the patient's condition. As an indication, a dose of 1 drop per eye, twice a day (morning and evening), at a concentration of 0.1% is the preferred one.

Claims (3)

CLAIMS 1. Mildronate, for use in the prevention or treatment of open angle glaucoma, where mildronate is administered in the form of eye drops and at a preferred dose of 0.01-0.5% is a dose of 0.025-0, 25; particularly preferred is a dose of 0.1%, and optionally one or more ophthalmologically acceptable diluents and / or excipients. 2. Mildronate of claim 1, wherein said eye drops are administered in a dose of at least one drop per eye twice a day. 3. Mildronate of the preceding claims, in the form of a physiological supplement or medicament.