WO2013060908A1 - Use of a melatonin analogue for the reduction of intraocular pressure - Google Patents

Use of a melatonin analogue for the reduction of intraocular pressure Download PDF

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Publication number
WO2013060908A1
WO2013060908A1 PCT/ES2012/000264 ES2012000264W WO2013060908A1 WO 2013060908 A1 WO2013060908 A1 WO 2013060908A1 ES 2012000264 W ES2012000264 W ES 2012000264W WO 2013060908 A1 WO2013060908 A1 WO 2013060908A1
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intraocular pressure
agomelatine
glaucoma
pharmaceutically acceptable
acceptable salts
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PCT/ES2012/000264
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Spanish (es)
French (fr)
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Jesús PINTOR JUST
Alejandro MARTÍNEZ ÁGUILA
Antonio BERGUA AZNAR
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Universidad Complutense De Madrid
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Publication of WO2013060908A1 publication Critical patent/WO2013060908A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention falls within the field of medicine or pharmacological treatment. More specifically, the described invention relates to a method for reducing intraocular pressure in a subject by the administration of a melatonin analogue, agomelatine. The invention also relates to the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure by administering an amount of agomelatine and / or pharmaceutically acceptable salts thereof effective to reduce intraocular pressure, in a patient, at levels where disease progression stops.
  • OHTS Ocular Hypertension Treatment Study
  • Glaucoma is an extraordinarily serious disease that can lead to a very severe loss of vision, or even blindness, in some cases with pain.
  • glaucoma There are several types of glaucoma, each of which has a different origin and evolution. Most types of glaucoma are characterized by high intraocular pressure which produces pathological changes in the optic disc, with the consequent appearance of various vision defects. However, there is also a variant of glaucoma - called normotensive glaucoma, or normal tension glaucoma, or low pressure glaucoma, or glaucoma without elevation of intraocular pressure - characterized by presenting intraocular pressure within normal values but where the nerve Optical suffers compression and deterioration of its fibers.
  • the treatment of all forms of glaucoma is the reduction of intraocular pressure to levels at which the progression of The disease stops.
  • the reduction of intraocular pressure is the main means to prevent irreversible damage caused by glaucoma.
  • melatonin (5-methoxy-N-acetyltryptamine) is a neurohormone secreted by the pineal gland that follows a circadian rhythm in its production and secretion into the bloodstream. The levels of this hormone increase in the blood with the sunset and have a maximum at 2 in the morning. Melatonin has been related to a significant number of aspects of medical research.
  • the treatment of Parkinson's disease, epilepsy or other behavioral disorders demonstrates the pharmacological potential of this substance.
  • the patent, US Pat. No. 3,642,994 describes the symptomatic treatment of said diseases by means of oral or parenteral administration of melatonin.
  • agomelatine is an analogue of melatonin and a potent agonist of the melatonin ⁇ and MT2 receptors and, with a lower affinity, inhibits the 5-HT2C receptor by associating an increase in the release of dopamine and norepinephrine in the frontal cortex, an area involved in humor, anxiety and cognition.
  • Agomelatine has no effect on the reuptake of other monoamines and has no affinity for benzodiazepine, histaminergic, adrenergic ⁇ or ⁇ , cholinergic receptors, or for dopaminergic receptors.
  • This melatonin analog is currently used as active substance for the treatment of depression.
  • agomelatine was authorized by the European Medicines Agency (EMA) in February 2009 and is approved for a single indication: the treatment of episodes of major depression in adults.
  • Agomelatine is marketed under two different trade names Valdoxan ® and Thymanax ® . Most of the side effects associated with agomelatine are mild or moderate. Most of them are transitory and do not entail abandoning treatment.
  • the described invention relates to a method for reducing intraocular pressure in a subject by administering an analogue of melatonin, agomelatine.
  • Agomelatine, N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide is an agonist of the melatonin ⁇ and MT 2 receptors.
  • a method for the reduction of intraocular pressure in a subject comprising the administration of agomelatine and / or pharmaceutically acceptable salts thereof is described.
  • the invention also relates to the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure, by administering an amount of agomelatine and / or pharmaceutically acceptable salts thereof effective to reduce intraocular pressure. , in a patient, at levels where the disease progression stops.
  • hypertensive glaucoma refers to that variety of glaucoma characterized by presenting an intraocular pressure greater than the normal values established for the animal species and race in question.
  • hypertensive glaucoma is that variety of glaucoma in which the patient has an intraocular pressure greater than 21.0 mm Hg.
  • the terms "normotensive glaucoma” or “normal tension glaucoma” or “low pressure glaucoma” or “glaucoma without intraocular pressure elevation” are equivalent and interchangeable and refer to that variety of glaucoma characterized by presenting an intraocular pressure inside of the normal values established for the animal species and race in question.
  • normotensive glaucoma is that variety of glaucoma in which the patient has an intraocular pressure less than or equal to 21.0 mm Hg.
  • high intraocular pressure or “high intraocular pressure” or “ocular hypertension” are equivalent and interchangeable and refer to any situation in which the subject's intraocular pressure has a value greater than the established normal values. for the animal species and race in question. In the case of Caucasian populations (white race) of the human being, high intraocular pressure or ocular hypertension is that situation in which the subject has an intraocular pressure greater than 21.0 mm Hg.
  • the terms "subject” or “patient” are equivalent and interchangeable and refer to any animal species that is capable of presenting an intraocular pressure value greater than the normal values established for that animal species and breed from which be treated, and / or be susceptible to glaucoma -in any of its varieties- and / or any disease characterized by high intraocular pressure.
  • animal species included within the scope of these expressions are the human being, mouse, rabbit, dog, cat and horse.
  • the invention described herein relates to a compound and pharmaceutical formulations thereof for use in reducing intraocular pressure in a subject.
  • the present specification also refers to a compound and pharmaceutical formulations thereof for use in the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure.
  • the The present invention relates to agomelatine and / or pharmaceutically acceptable salts thereof and pharmaceutical formulations thereof for use in reducing infraocular pressure.
  • Another aspect of the present invention relates to agomelatine and / or pharmaceutically acceptable salts thereof and pharmaceutical formulations thereof for use in the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure. .
  • the present specification claims a method for reducing intraocular pressure in a subject.
  • Another aspect of the invention claims a method for treating and / or preventing hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure, in a patient. More particularly, the present specification refers to a method for reducing intraocular pressure using agomelatine, N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, and / or pharmaceutically acceptable salts thereof, in a subject.
  • Another aspect of the present specification refers to a method for treating and / or preventing hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure using agomelatine, N- [2- (7-methoxynaphthalen-1-yl) ethyl ] acetamide, and / or pharmaceutically acceptable salts thereof, in a patient.
  • the present invention is described as a method for reducing infraocular pressure, through the application of agomelatine and / or pharmaceutically acceptable salts thereof, as well as the methods of using said compounds in the treatment and / or prevention of hypertensive glaucoma. or normotense and / or diseases characterized by high intraocular pressure.
  • agomelatine N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide
  • N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide is characterized by specifically binding to MT-i and MT 2 type melatonin receptors (Audinot, V ., Mailliet, F., Lahaye-Brasseur, C, Bonnaud, A., Le Gall, A., Amosse, C, Dromaint, S., Rodriguez, M., Nagel, N., Galizzi, JP, Malpaux, B ., Nicolast, G., Lesieur, D., Lefoulon, F., Renard, P., Delagrange, P., Boutin, JA, 2003. New selective ligands of human cloned melatonin MT and MT 2 receptors Naunyn Schmiedebergs Arch. Pharmacol. 367, 553-561.)
  • N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, also called agomelatine, and / or pharmaceutically acceptable salts thereof for the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure is justified thanks to the ability of agomelatine and / or pharmaceutically acceptable salts thereof to reduce intraocular pressure in a subject (or hypotensive capacity).
  • agomelatine and / or pharmaceutically acceptable salts thereof to reduce intraocular pressure in a subject is claimed.
  • N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide also called agomelatine
  • pharmaceutically acceptable salts thereof are claimed herein for use in reducing intraocular pressure as well as in the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure, in a patient.
  • the use of N- [2- (7-methoxynaphthalen-1- yl) ethyl] acetamide, also called omelatin, of the formula (I) is claimed.
  • a medicament intended for the reduction of intraocular pressure in a subject is claimed.
  • N- [2- (7- methoxynaphthalen-1-yl) ethyl] acetamide, also called agomelatine, and / or pharmaceutically acceptable salts thereof for the preparation is claimed.
  • a medicament intended to reduce intraocular pressure for the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure More particularly, diseases characterized by high intraocular pressure are selected from the group comprised of ocular infections, ocular inflammations, uveitis and diabetic retinopathy.
  • Another aspect of the present specification refers to the fact that the medicament is administered in an effective prophylactic and / or therapeutic amount and is adapted for administration by a route selected from the group comprised by the topical, oral, sublingual, rectal, intradermal routes. , subcutaneous, intramuscular, intravenous, intracardiac, intrarachial, intraarticular, percutaneous or transdermal, and inhaled.
  • the medicament is administered topically, whether or not the compound is vehiculized.
  • Hyposomes and presents a pharmaceutical form selected from the group comprised of solutions, suspensions, emulsions, eye drops, liquid drops, liquid washes, gels, creams, ointments, ointments and sprays.
  • Another aspect of the invention relates to an assay specifically designed to demonstrate the efficacy of agomelatine and / or pharmaceutically acceptable salts thereof in reducing infraocular pressure in a subject (also called hypotensive efficacy).
  • agomelatine and / or pharmaceutically acceptable salts thereof in the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure is also evidenced by the described assay.
  • the essay comprises three main stages. First, the intraocular pressure of the animal species chosen for the test is measured. Secondly, a pharmaceutical formulation of agomelatine and / or pharmaceutically acceptable salts thereof is prepared and administered to the animal species in question. Thirdly, and once the pharmaceutical composition is administered, the intraocular pressure is measured from time to time to observe its variation over time. This test is repeated for different concentrations of agomelatine and / or pharmaceutically acceptable salts thereof.
  • FIG. 1 This graph presents a comparison of the evolution of the value of intraocular pressure (IOP) between the control group and the treatment group, from half an hour before the administration of the pharmaceutical formulation to six hours after the administration.
  • IOP intraocular pressure
  • the administration of agomelatine in an albino rabbit from New Zealand following the procedure described in example 1 of the "Embodiment of the invention” section is capable of achieving a reduction in intraocular pressure of 21 % 180 minutes after administration, recovering the initial value of intraocular pressure again 360 minutes after administration of the formulation.
  • FIG. 2 This graph shows how the effect of agomelatine in an albino rabbit in New Zealand varies depending on the concentration administered by it, or in other words, the dose-response curve of agomelatine.
  • EC 50 6.93 * 10 "11 M.
  • the pharmaceutical formulation of agomelatine to be administered of the present invention was prepared by dissolving 2433 g of the compound in 1000 ⁇ _dimethyl sulfoxide (DMSO), preparing a concentrated solution of the active ingredient (stock solution). This previous stage had to be carried out since agomelatine is not soluble in aqueous solutions. 10 ⁇ _ of this concentrated solution was mixed with 990 ⁇ _ of saline solution (0.9% NaCl), obtaining a final solution of 100 ⁇ concentration, which would constitute the final pharmaceutical formulation of agomelatine to be administered.
  • DMSO dimethyl sulfoxide
  • a specific trial was designed to evaluate the safety and efficacy of agomelatine as an intraocular pressure reducing agent.
  • the designed trial comprised three main stages:
  • Stage a first, measurement of the intraocular pressure of the animal species chosen for the test,
  • Stage b secondly, preparation of a pharmaceutical formulation of agomelatine and administration thereof to the animal species in question
  • Stage c thirdly, and once the pharmaceutical composition is administered, measurement of intraocular pressure from time to time to observe its variation over time.
  • the experimental model for the albino rabbit test in New Zealand was chosen as the experimental model.
  • a sample of 7 normotensive rabbits was used (the normal intraocular pressure established for this animal species ranges between 9.0 and 10.0 mm Hg) of which one of them was randomly assigned to the control group and the rest were assigned to the group of treatment.
  • the rest of the values measured in both the control rabbit and the rabbits in the treatment group were normalized with respect to that value of 100%.
  • Stage b Each rabbit in the treatment group 10 ⁇ of the final formulation of agomelatine prepared by following the procedure described in section A of this section in the form of drops was administered topically.
  • the control rabbit was administered 10 ⁇ topically by ocular route of a pharmaceutical formulation of exactly the same composition as the one administered to the
  • the pharmaceutical formulation was prepared by mixing 990 ⁇ _ of saline (0.9% NaCl) with 10 pL of DMSO to obtain a saline solution with 1% of DMSO, of which 10 pL was taken for application in the rabbit's eye.
  • agomelatine was studied in terms of% of intra-cutaneous pressure reached with respect to the reference value (100%) in each of the moments in which an intra-cucumber pressure measurement was made.
  • agomelatine To obtain information on the pharmacodynamics of agomelatine, the test was repeated for different concentrations of agomelatine in the pharmaceutical formulation to be administered.
  • each trial was performed three times in three consecutive weeks, leaving a period of one week between trial and trial for the rabbit to recover the initial intraocular pressure value so that the initial conditions in those three essays they were the same.
  • the pharmaceutical formulation of agomelatine was administered to the six rabbits in succession and always respecting the same order of administration.
  • Each of the intraocuous pressure measurements was performed in triplicate, establishing as a final value the average of these three values.
  • Figure 1 shows a comparison of the evolution of the value of intraocuitary pressure (IOP) between the control group and the treatment group, from half an hour before the administration of the pharmaceutical formulation to six hours. after administration
  • IOP intraocuitary pressure

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Abstract

The invention relates to the reduction of intraocular pressure by means of a melatonin analogue. The present invention describes a method for reducing intraocular pressure by administering a pharmaceutical formulation of the commercially available substance agomelatine, N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide, and/or pharmaceutically acceptable salts thereof. The present invention also claims the use of agomelatine and/or pharmaceutically acceptable salts thereof for the preparation of a drug intended for the treatment and/or prevention of hypertensive and/or normotensive glaucoma and/or diseases characterised by high intraocular pressure. Said drug is preferably administered by the topical route, optionally carried by liposomes, and can be presented in various pharmaceutical forms, such as solutions, suspensions, emulsions, eye drops, liquid drops, liquid washes, gels, creams, ointments, lotions and sprays.

Description

Uso de un análogo de la melatonina para la reducción de la presión intraocular  Use of a melatonin analog for the reduction of intraocular pressure
Sector de la técnica Technical sector
La presente invención se encuadra dentro del campo de la medicina o del tratamiento farmacológico. Más específicamente, la invención descrita se refiere a un método para reducir la presión intraocular en un sujeto mediante la administración de un análogo de la melatonina, la agomelatina. La invención también se refiere al tratamiento y/o prevención del glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular mediante la administración de una cantidad de agomelatina y/o sales farmacéuticamente aceptables de la misma eficaz para reducir la presión intraocular, en un paciente, a niveles en que la progresión de la enfermedad se detenga. The present invention falls within the field of medicine or pharmacological treatment. More specifically, the described invention relates to a method for reducing intraocular pressure in a subject by the administration of a melatonin analogue, agomelatine. The invention also relates to the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure by administering an amount of agomelatine and / or pharmaceutically acceptable salts thereof effective to reduce intraocular pressure, in a patient, at levels where disease progression stops.
Estado de la técnica State of the art
La población de las distintas regiones del mundo presenta una serie de características físicas comunes, que son consecuencia de factores tales como la herencia genética y las influencias medioambientales. Desde el punto de vista de la oftalmología, estos puntos en común incluyen el tamaño del globo ocular, la refracción y la presión intraocular (PIO). En el caso de poblaciones caucásicas (raza blanca), la presión intraocular normal oscila entre 10,0 mm Hg y 21 ,0 mm Hg. Aunque no existe una frontera estricta, se considera que 21 ,0 mm Hg es el límite superior de la normalidad y toda medida que supere los 21 ,0 mm Hg es etiquetada como "hipertensión ocular" y también como "sospecha de glaucoma".  The population of the different regions of the world presents a series of common physical characteristics, which are a consequence of factors such as genetic inheritance and environmental influences. From the point of view of ophthalmology, these points in common include the size of the eyeball, refraction and intraocular pressure (IOP). In the case of Caucasian populations (white race), normal intraocular pressure ranges between 10.0 mm Hg and 21.0 mm Hg. Although there is no strict border, 21.0 mm Hg is considered to be the upper limit of normal and any measure that exceeds 21.0 mm Hg is labeled as "ocular hypertension" and also as "suspected glaucoma."
El estudio OHTS (Ocular Hypertension Treatment Study) estableció que la reducción de la presión intraocular en hipertensos oculares puede retrasar e incluso prevenir el desarrollo de glaucoma. El estudio sugirió que alrededor del 90% de hipertensos oculares deberían ser tratados y observados a lo largo del tiempo. The OHTS (Ocular Hypertension Treatment Study) study established that reducing intraocular pressure in ocular hypertensives may delay and even prevent the development of glaucoma. The study suggested that about 90% of ocular hypertensives should be treated and observed over time.
El glaucoma es una enfermedad extraordinariamente grave que puede llevar a una muy severa pérdida de la visión, o incluso a la ceguera, cursando en algunos casos con dolor. Glaucoma is an extraordinarily serious disease that can lead to a very severe loss of vision, or even blindness, in some cases with pain.
Existen varios tipos de glaucoma, cada uno de los cuales tiene un origen y una evolución diferentes. La mayor parte de los tipos de glaucoma se caracteriza por una elevada presión intraocular la cual produce cambios patológicos en el disco óptico, con la consecuente aparición de diversos defectos en la visión. Sin embargo, existe también una variante del glaucoma -denominada glaucoma normotenso, o glaucoma de tensión normal, o glaucoma de baja presión, o glaucoma sin elevación de la presión intraocular- caracterizada por presentar una presión intraocular dentro de los valores normales pero donde el nervio óptico sufre la compresión y el deterioro de sus fibras. There are several types of glaucoma, each of which has a different origin and evolution. Most types of glaucoma are characterized by high intraocular pressure which produces pathological changes in the optic disc, with the consequent appearance of various vision defects. However, there is also a variant of glaucoma - called normotensive glaucoma, or normal tension glaucoma, or low pressure glaucoma, or glaucoma without elevation of intraocular pressure - characterized by presenting intraocular pressure within normal values but where the nerve Optical suffers compression and deterioration of its fibers.
El tratamiento de todas las formas de glaucoma, tanto si se trata del glaucoma caracterizado por una elevada presión intraocular, también llamado glaucoma hipertenso, como si se trata del glaucoma normotenso, consiste en la reducción de la presión intraocular a niveles en que la progresión de la enfermedad se detenga. La reducción de la presión intraocular es el medio principal para prevenir los irreversibles daños causados por el glaucoma. The treatment of all forms of glaucoma, whether it is glaucoma characterized by high intraocular pressure, also called hypertensive glaucoma, or if it is normotensive glaucoma, is the reduction of intraocular pressure to levels at which the progression of The disease stops. The reduction of intraocular pressure is the main means to prevent irreversible damage caused by glaucoma.
En la actualidad, para el tratamiento del glaucoma se cuenta con fármacos que disminuyen la producción de humor acuoso o incrementan su velocidad de reabsorción. Los más usados en la actualidad son los parasimpaticomiméticos, los agonistas de los receptores alfa2, los beta-bloqueantes, los inhibidores de la anhidrasa carbónica y los análogos de las prostaglandinas, pero ninguno de ellos está exento de ciertos efectos secundarios tales como visión borrosa, taquicardias o arritmias. Currently, for the treatment of glaucoma there are drugs that decrease the production of aqueous humor or increase its speed of reabsorption. The most commonly used are parasympathomimetics, alpha2 receptor agonists, beta-blockers, carbonic anhydrase inhibitors and prostaglandin analogs, but none of them are free of certain side effects such as blurred vision, tachycardias or arrhythmias.
En la búsqueda de nuevas sustancias más eficaces y con menos efectos secundarios para el tratamiento del glaucoma se han ensayado nuevas moléculas, tanto naturales como sintéticas. Una de las moléculas de origen natural estudiada y ensayada es la melatonina. La melatonina (5-metoxi-N-acetiltriptamina) es una neurohormona secretada por la glándula pineal que sigue un ritmo circadiano en su producción y secreción al torrente sanguíneo. Los niveles de esta hormona aumentan en la sangre con el atardecer y tienen un máximo a las 2 de la mañana. La melatonina ha sido relacionada con un número importante de aspectos de investigación médica. El tratamiento de la enfermedad de Parkinson, epilepsia u otros desórdenes del comportamiento, demuestran el potencial farmacológico de esta sustancia. Por ejemplo, la patente, U.S. Pat. No. 3,642,994 describe el tratamiento sintomático de las mencionadas enfermedades por medio de la administración oral o parenteral de melatonina. In the search for new, more effective substances with fewer side effects for the treatment of glaucoma, new molecules, both natural and synthetic, have been tested. One of the molecules of natural origin studied and tested is melatonin. Melatonin (5-methoxy-N-acetyltryptamine) is a neurohormone secreted by the pineal gland that follows a circadian rhythm in its production and secretion into the bloodstream. The levels of this hormone increase in the blood with the sunset and have a maximum at 2 in the morning. Melatonin has been related to a significant number of aspects of medical research. The treatment of Parkinson's disease, epilepsy or other behavioral disorders demonstrates the pharmacological potential of this substance. For example, the patent, US Pat. No. 3,642,994 describes the symptomatic treatment of said diseases by means of oral or parenteral administration of melatonin.
El tratamiento con melatonina de distintas patologías en diferentes modelos de experimentación ha puesto de manifiesto la presencia de esta neurohormona en el espacio intraocular. La bibliografía y artículos científicos publicados desde finales del siglo pasado recogen resultados contradictorios respecto a la acción que ejerce la melatonina sobre la presión intraocular. Una serie de publicaciones sugieren que la melatonina podría elevar la presión intraocular (J. Pineal Res., Vol. 1 , page 3, 1984; Ophthal. Res., 16:302-306, 1984), mientras que otras apuntan a justo lo contrario, es decir, señalan a la melatonina como potencial agente reductor de la presión intraocular. A raíz de esta disparidad de resultados y tras un estudio sobre el tema, Osborne postula que gran parte de la controversia se debe a dos grandes factores, por un lado el modo de administración de esta sustancia y por otro lado las diferentes especies en las que se ha ensayado (Acta Neurobiol. Exp. Warsz, vol. 54, 57-64, 1994). Treatment with melatonin of different pathologies in different experimental models has revealed the presence of this neurohormone in the intraocular space. The bibliography and scientific articles published since the end of the last century show contradictory results regarding the action that melatonin exerts on intraocular pressure. A series of publications suggest that melatonin could raise intraocular pressure (J. Pineal Res., Vol. 1, page 3, 1984; Ophthal. Res., 16: 302-306, 1984), while others point to just what On the contrary, that is, they point to melatonin as a potential intraocular pressure reducing agent. Following this disparity of results and after a study on the subject, Osborne postulates that much of the controversy is due to two major factors, on the one hand the mode of administration of this substance and on the other hand the different species in which It has been tested (Acta Neurobiol. Exp. Warsz, vol. 54, 57-64, 1994).
Por otra parte, la agomelatina es un análogo de la melatonina y un potente agonista de los receptores de la melatonina ΜΤΊ y MT2 y, con una menor afinidad, inhibe el receptor 5-HT2C asociando un incremento de la liberación de dopamina y noradrenalina en la corteza frontal, un área involucrada en el humor, ansiedad y la cognición. La agomelatina carece de efectos sobre la recaptación de otras monoaminas y no posee afinidad por receptores benzodiazepínicos, histaminérgicos, adrenérgicos α o β, colinérgicos, ni por los receptores dopaminérgicos. Este análogo de la melatonina se emplea actualmente como principio activo para el tratamiento de la depresión. La comercialización de la agomelatina fue autorizada por la European Medicines Agency (EMA) en febrero del año 2009 y está aprobada para una única indicación: el tratamiento de episodios de depresión mayor en adultos. La agomelatina se comercializa bajo dos nombres comerciales distintos Valdoxan® y Thymanax®. La mayor parte de los efectos secundarios asociados a agomelatina son leves o moderados. La mayor parte de ellos son transitorios y no conllevan el abandono del tratamiento. On the other hand, agomelatine is an analogue of melatonin and a potent agonist of the melatonin ΜΤΊ and MT2 receptors and, with a lower affinity, inhibits the 5-HT2C receptor by associating an increase in the release of dopamine and norepinephrine in the frontal cortex, an area involved in humor, anxiety and cognition. Agomelatine has no effect on the reuptake of other monoamines and has no affinity for benzodiazepine, histaminergic, adrenergic α or β, cholinergic receptors, or for dopaminergic receptors. This melatonin analog is currently used as active substance for the treatment of depression. The commercialization of agomelatine was authorized by the European Medicines Agency (EMA) in February 2009 and is approved for a single indication: the treatment of episodes of major depression in adults. Agomelatine is marketed under two different trade names Valdoxan ® and Thymanax ® . Most of the side effects associated with agomelatine are mild or moderate. Most of them are transitory and do not entail abandoning treatment.
Explicación de la invención Explanation of the invention.
La invención descrita se refiere a un método para reducir la presión intraocular en un sujeto mediante la administración de un análogo de la melatonina, la agomelatina. La agomelatina, N-[2-(7-metoxinaftalen-1-il)etil]acetamida, es un agonista de los receptores de la melatonina ΜΤΊ y MT2. En la presente invención se describe un método para la reducción de la presión intraocular en un sujeto que comprende la administración de agomelatina y/o sales farmacéuticamente aceptables de la misma. La invención también se refiere al tratamiento y/o prevención del glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular, mediante la administración de una cantidad de agomelatina y/o sales farmacéuticamente aceptables de la misma eficaz para reducir la presión intraocular, en un paciente, a niveles en que la progresión de la enfermedad se detenga. The described invention relates to a method for reducing intraocular pressure in a subject by administering an analogue of melatonin, agomelatine. Agomelatine, N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, is an agonist of the melatonin ΜΤΊ and MT 2 receptors. In the present invention a method for the reduction of intraocular pressure in a subject comprising the administration of agomelatine and / or pharmaceutically acceptable salts thereof is described. The invention also relates to the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure, by administering an amount of agomelatine and / or pharmaceutically acceptable salts thereof effective to reduce intraocular pressure. , in a patient, at levels where the disease progression stops.
En la presente invención, la expresión "glaucoma hipertenso" se refiere a aquella variedad del glaucoma caracterizada por presentar una presión intraocular superior a los valores normales establecidos para la especie animal y raza de la que se trate. En el caso de poblaciones caucásicas (raza blanca) del ser humano, glaucoma hipertenso es aquella variedad del glaucoma en la que el paciente presenta una presión intraocular superior a 21 ,0 mm Hg. En la presente invención, las expresiones "glaucoma normotenso" o "glaucoma de tensión normal" o "glaucoma de baja presión" o "glaucoma sin elevación de la presión intraocular" son equivalentes e intercambiables y se refieren a aquella variedad del glaucoma caracterizada por presentar una presión intraocular dentro de los valores normales establecidos para la especie animal y raza de la que se trate. En el caso de poblaciones caucásicas (raza blanca) del ser humano, glaucoma normotenso es aquella variedad del glaucoma en la que el paciente presenta una presión intraocular inferior o igual a 21 ,0 mm Hg. In the present invention, the term "hypertensive glaucoma" refers to that variety of glaucoma characterized by presenting an intraocular pressure greater than the normal values established for the animal species and race in question. In the case of Caucasian populations (white race) of the human being, hypertensive glaucoma is that variety of glaucoma in which the patient has an intraocular pressure greater than 21.0 mm Hg. In the present invention, the terms "normotensive glaucoma" or "normal tension glaucoma" or "low pressure glaucoma" or "glaucoma without intraocular pressure elevation" are equivalent and interchangeable and refer to that variety of glaucoma characterized by presenting an intraocular pressure inside of the normal values established for the animal species and race in question. In the case of Caucasian populations (white race) of the human being, normotensive glaucoma is that variety of glaucoma in which the patient has an intraocular pressure less than or equal to 21.0 mm Hg.
En la presente invención, las expresiones "elevada presión intraocular" o "presión intraocular elevada" o "hipertensión ocular" son equivalentes e intercambiables y se refieren a cualquier situación en la que la presión intraocular del sujeto presenta un valor superior a los valores normales establecidos para la especie animal y raza de la que se trate. En el caso de poblaciones caucásicas (raza blanca) del ser humano, elevada presión intraocular o hipertensión ocular es aquella situación en la que el sujeto presenta una presión intraocular superior a 21 ,0 mm Hg. En la presente invención, las expresiones "sujeto" o "paciente" son equivalentes e intercambiables y se refieren a cualquier especie animal que sea susceptible de presentar un valor de presión intraocular superior a los valores normales establecidos para esa especie animal y raza de la que se trate, y/o sea susceptible de padecer glaucoma -en cualquiera de sus variedades- y/o cualquier enfermedad caracterizada por una elevada presión intraocular. Ejemplos de especies animales incluidas dentro del alcance de estas expresiones son el ser humano, ratón, conejo, perro, gato y caballo. In the present invention, the terms "high intraocular pressure" or "high intraocular pressure" or "ocular hypertension" are equivalent and interchangeable and refer to any situation in which the subject's intraocular pressure has a value greater than the established normal values. for the animal species and race in question. In the case of Caucasian populations (white race) of the human being, high intraocular pressure or ocular hypertension is that situation in which the subject has an intraocular pressure greater than 21.0 mm Hg. In the present invention, the terms "subject" or "patient" are equivalent and interchangeable and refer to any animal species that is capable of presenting an intraocular pressure value greater than the normal values established for that animal species and breed from which be treated, and / or be susceptible to glaucoma -in any of its varieties- and / or any disease characterized by high intraocular pressure. Examples of animal species included within the scope of these expressions are the human being, mouse, rabbit, dog, cat and horse.
Se debe tener en cuenta que el uso en esta descripción y en las reivindicaciones de los artículos el/la, un/a/o incluye la referencia al plural a no ser que en el contexto se indique explícitamente lo contrario. It should be borne in mind that the use in this description and in the claims of the articles el / la, a / a / o includes the reference to the plural unless otherwise explicitly stated in the context.
La invención que aquí se describe se refiere a un compuesto y a formulaciones farmacéuticas del mismo para su uso en la reducción de la presión intraocular en un sujeto. La presente memoria se refiere también a un compuesto y a formulaciones farmacéuticas del mismo para su uso en el tratamiento y/o prevención del glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular. De un modo más particular, la presente invención se refiere a agomelatina y/o sales farmacéuticamente aceptables de la misma y a formulaciones farmacéuticas de las mismas para su uso en la reducción de la presión infraocular. Otro aspecto de la presente invención se refiere a agomelatina y/o sales farmacéuticamente aceptables de la misma y a formulaciones farmacéuticas de las mismas para su uso en el tratamiento y/o prevención del glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular. The invention described herein relates to a compound and pharmaceutical formulations thereof for use in reducing intraocular pressure in a subject. The present specification also refers to a compound and pharmaceutical formulations thereof for use in the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure. In a more particular way, the The present invention relates to agomelatine and / or pharmaceutically acceptable salts thereof and pharmaceutical formulations thereof for use in reducing infraocular pressure. Another aspect of the present invention relates to agomelatine and / or pharmaceutically acceptable salts thereof and pharmaceutical formulations thereof for use in the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure. .
La presente memoria reivindica un método para reducir la presión intraocular en un sujeto. Otro aspecto de la invención reivindica un método para tratar y/o prevenir el glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular, en un paciente. De modo más particular, la presente memoria se refiere a un método para reducir la presión intraocular usando agomelatina, N-[2-(7-metoxinaftalen-1-il)etil]acetamida, y/o sales farmacéuticamente aceptables de la misma, en un sujeto. Otro aspecto de la presente memoria se refiere a un método para tratar y/o prevenir el glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular usando agomelatina, N-[2-(7-metoxinaftalen-1-il)etil]acetamida, y/o sales farmacéuticamente aceptables de la misma, en un paciente. The present specification claims a method for reducing intraocular pressure in a subject. Another aspect of the invention claims a method for treating and / or preventing hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure, in a patient. More particularly, the present specification refers to a method for reducing intraocular pressure using agomelatine, N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, and / or pharmaceutically acceptable salts thereof, in a subject. Another aspect of the present specification refers to a method for treating and / or preventing hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure using agomelatine, N- [2- (7-methoxynaphthalen-1-yl) ethyl ] acetamide, and / or pharmaceutically acceptable salts thereof, in a patient.
La presente invención se describe como un método para reducir la presión infraocular, por medio de la aplicación de agomelatina y/o sales farmacéuticamente aceptables de la misma, así como los métodos de uso de dichos compuestos en el tratamiento y/o prevención del glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular. The present invention is described as a method for reducing infraocular pressure, through the application of agomelatine and / or pharmaceutically acceptable salts thereof, as well as the methods of using said compounds in the treatment and / or prevention of hypertensive glaucoma. or normotense and / or diseases characterized by high intraocular pressure.
La sustancia a la que se hace referencia en la presente invención, la agomelatina, N-[2-(7-metoxinaftalen-1-il)etil]acetamida, viene descrita por la siguiente formula (I):
Figure imgf000008_0001
The substance referred to in the present invention, agomelatine, N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, is described by the following formula (I):
Figure imgf000008_0001
OCHÍ3 EIGHT3
(i)  (i)
El compuesto N-[2-(7-metox¡naftalen-1-il)etil]acetamida, también llamado agomelatina, se caracteriza por unirse de modo específico a los receptores de melatonina del tipo MT-i y MT2 (Audinot, V., Mailliet, F., Lahaye-Brasseur, C, Bonnaud, A., Le Gall, A., Amosse, C, Dromaint, S., Rodríguez, M., Nagel, N., Galizzi, J.P., Malpaux, B., Guillaumet, G., Lesieur, D., Lefoulon, F., Renard, P., Delagrange, P., Boutin, J.A., 2003. New selective ligands of human cloned melatonin ΜΤΊ and MT2 receptors. Naunyn Schmiedebergs Arch. Pharmacol. 367, 553-561.)· The compound N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, also called agomelatine, is characterized by specifically binding to MT-i and MT 2 type melatonin receptors (Audinot, V ., Mailliet, F., Lahaye-Brasseur, C, Bonnaud, A., Le Gall, A., Amosse, C, Dromaint, S., Rodriguez, M., Nagel, N., Galizzi, JP, Malpaux, B ., Guillaumet, G., Lesieur, D., Lefoulon, F., Renard, P., Delagrange, P., Boutin, JA, 2003. New selective ligands of human cloned melatonin MT and MT 2 receptors Naunyn Schmiedebergs Arch. Pharmacol. 367, 553-561.)
El uso de la N-[2-(7-metoxinaftalen-1-il)etil]acetamida, también llamada agomelatina, y/o sales farmacéuticamente aceptables de la misma para el tratamiento y/o prevención del glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular se justifica gracias a la capacidad que presenta la agomelatina y/o sales farmacéuticamente aceptables de la misma de reducir la presión intraocular en un sujeto (o capacidad hipotensora). En la presente invención se reivindica la capacidad de la agomelatina y/o sales farmacéuticamente aceptables de la misma de reducir la presión intraocular en un sujeto. The use of N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, also called agomelatine, and / or pharmaceutically acceptable salts thereof for the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure is justified thanks to the ability of agomelatine and / or pharmaceutically acceptable salts thereof to reduce intraocular pressure in a subject (or hypotensive capacity). In the present invention, the ability of agomelatine and / or pharmaceutically acceptable salts thereof to reduce intraocular pressure in a subject is claimed.
En la presente memoria se reivindican distintas formulaciones farmacéuticas de N-[2-(7-metoxinaftalen-1-il)etil]acetam¡da, también llamada agomelatina, y/o sales farmacéuticamente aceptables de la misma para su uso en la reducción de la presión intraocular así como en el tratamiento y/o prevención del glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular, en un paciente. En la presente invención se reivindica el uso de N-[2-(7-metoxinaftalen-1- il)etil]acetamida, también llamada a omelatina, de la fórmula (I) Various pharmaceutical formulations of N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, also called agomelatine, and / or pharmaceutically acceptable salts thereof are claimed herein for use in reducing intraocular pressure as well as in the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure, in a patient. In the present invention the use of N- [2- (7-methoxynaphthalen-1- yl) ethyl] acetamide, also called omelatin, of the formula (I) is claimed.
Figure imgf000009_0001
Figure imgf000009_0001
y/o sales farmacéuticamente aceptables de la misma para la preparación de un medicamento destinado a la reducción de la presión intraocular en un sujeto. De un modo particular, en la presente invención, se reivindica el uso de la N-[2-(7- metoxinaftalen-1-il)etil]acetamida, también llamada agomelatina, y/o sales farmacéuticamente aceptables de la misma para la preparación de un medicamento destinado a la reducción de la presión intraocular para el tratamiento y/o prevención del glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular. De manera más particular, las enfermedades caracterizadas por una elevada presión intraocular se seleccionan del grupo comprendido por infecciones oculares, inflamaciones oculares, uveítis y retinopatía diabética. Otro aspecto de la presente memoria se refiere al hecho de que el medicamento se administra en una cantidad profiláctica y/o terapéutica eficaz y está adaptado para su administración por una vía seleccionada del grupo comprendido por las vías tópica, oral, sublingual, rectal, intradérmica, subcutánea, intramuscular, endovenosa, intracardíaca, intraraquídea, intraarticular, percutánea o transdérmica, e inhalada. and / or pharmaceutically acceptable salts thereof for the preparation of a medicament intended for the reduction of intraocular pressure in a subject. Particularly, in the present invention, the use of N- [2- (7- methoxynaphthalen-1-yl) ethyl] acetamide, also called agomelatine, and / or pharmaceutically acceptable salts thereof for the preparation is claimed. of a medicament intended to reduce intraocular pressure for the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure. More particularly, diseases characterized by high intraocular pressure are selected from the group comprised of ocular infections, ocular inflammations, uveitis and diabetic retinopathy. Another aspect of the present specification refers to the fact that the medicament is administered in an effective prophylactic and / or therapeutic amount and is adapted for administration by a route selected from the group comprised by the topical, oral, sublingual, rectal, intradermal routes. , subcutaneous, intramuscular, intravenous, intracardiac, intrarachial, intraarticular, percutaneous or transdermal, and inhaled.
En un modo de realización de la presente invención, el medicamento se administra por vía tópica, estando el compuesto vehiculizado o no mediante Hposomas, y presenta una forma farmacéutica seleccionada del grupo comprendido por soluciones, suspensiones, emulsiones, colirios, gotas de líquido, lavados de líquido, geles, cremas, ungüentos, pomadas y sprays. Otro aspecto de la invención se refiere a un ensayo específicamente diseñado para demostrar la eficacia de la agomelatina y/o sales farmacéuticamente aceptables de la misma en la reducción de la presión infraocular en un sujeto (también llamada eficacia hipotensora). Consecuentemente, mediante el ensayo descrito queda también de manifiesto la eficacia de la agomelatina y/o sales farmacéuticamente aceptables de la misma en el tratamiento y/o prevención del glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular. In one embodiment of the present invention, the medicament is administered topically, whether or not the compound is vehiculized. Hyposomes, and presents a pharmaceutical form selected from the group comprised of solutions, suspensions, emulsions, eye drops, liquid drops, liquid washes, gels, creams, ointments, ointments and sprays. Another aspect of the invention relates to an assay specifically designed to demonstrate the efficacy of agomelatine and / or pharmaceutically acceptable salts thereof in reducing infraocular pressure in a subject (also called hypotensive efficacy). Consequently, the efficacy of agomelatine and / or pharmaceutically acceptable salts thereof in the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure is also evidenced by the described assay.
El ensayo comprende tres etapas principales. En primer lugar, se mide la presión intraocular de la especie animal elegida para el ensayo. En segundo lugar, se prepara una formulación farmacéutica de agomelatina y/o sales farmacéuticamente aceptables de la misma y se administra a la especie animal en cuestión. En tercer lugar, y una vez administrada la composición farmacéutica, se mide la presión intraocular cada cierto tiempo para observar su variación a lo largo del tiempo. Este ensayo se repite para distintas concentraciones de agomelatina y/o sales farmacéuticamente aceptables de la misma. The essay comprises three main stages. First, the intraocular pressure of the animal species chosen for the test is measured. Secondly, a pharmaceutical formulation of agomelatine and / or pharmaceutically acceptable salts thereof is prepared and administered to the animal species in question. Thirdly, and once the pharmaceutical composition is administered, the intraocular pressure is measured from time to time to observe its variation over time. This test is repeated for different concentrations of agomelatine and / or pharmaceutically acceptable salts thereof.
A partir de los datos obtenidos con las distintas mediciones es posible construir distintas curvas, por ejemplo, la curva que muestra el efecto del principio activo a lo largo del tiempo y la curva dosis-respuesta. Mediante estas curvas se puede determinar la farmacodinamia del principio activo, es decir, determinar cómo varía el efecto del principio activo con el tiempo y cuál es la dosis efectiva y la forma correcta de administración del fármaco en la especie animal concreta sobre la que se está trabajando. From the data obtained with the different measurements it is possible to construct different curves, for example, the curve that shows the effect of the active principle over time and the dose-response curve. Through these curves the pharmacodynamics of the active substance can be determined, that is, to determine how the effect of the active ingredient varies over time and what is the effective dose and the correct way of administration of the drug in the specific animal species on which it is being working.
De forma más concreta, a partir de los datos recogidos en el ensayo se puede sacar información sobre qué reducción de presión intraocular se obtiene respecto al valor inicial, cuánto tarda en alcanzarse ese valor máximo de reducción de presión infraocular, durante cuánto tiempo se mantiene ese valor mínimo de presión alcanzado y a partir de qué instante comienza a elevarse de nuevo la presión intraocular. De manera más particular, se eligió para el ensayo al conejo albino de Nueva Zelanda como modelo experimental y se midió la presión intraocular de su(s) ojo(s) antes y después de la administración de la formulación farmacéutica de agomelatina preparada. Descripción de las figuras More specifically, from the data collected in the test, information can be obtained on what reduction of intraocular pressure is obtained with respect to the initial value, how long it takes to reach that maximum value of reduction of infraocular pressure, for how long that minimum value of pressure reached is maintained and from what moment the intraocular pressure begins to rise again. More particularly, the New Zealand albino rabbit was chosen for the test as an experimental model and the intraocular pressure of its eye (s) was measured before and after administration of the pharmaceutical formulation of agomelatine prepared. Description of the figures
Figura 1 : En este gráfico se presenta una comparativa de la evolución del valor de la presión intraocular (PIO) entre el grupo de control y el grupo de tratamiento, desde media hora antes de la administración de la formulación farmacéutica hasta seis horas después de la administración. Según la información proporcionada por la gráfica, la administración de agomelatina en un conejo albino de Nueva Zelanda siguiendo el procedimiento descrito en el ejemplo 1 de la sección "Modo de realización de la invención" es capaz de conseguir una reducción de la presión intraocular del 21% a los 180 minutos de la administración, volviendo a recuperar el valor inicial de presión intraocular a los 360 minutos de la administración de la formulación.  Figure 1: This graph presents a comparison of the evolution of the value of intraocular pressure (IOP) between the control group and the treatment group, from half an hour before the administration of the pharmaceutical formulation to six hours after the administration. According to the information provided by the graph, the administration of agomelatine in an albino rabbit from New Zealand following the procedure described in example 1 of the "Embodiment of the invention" section is capable of achieving a reduction in intraocular pressure of 21 % 180 minutes after administration, recovering the initial value of intraocular pressure again 360 minutes after administration of the formulation.
Figura 2: Este gráfico muestra cómo varía el efecto de la agomelatina en un conejo albino de Nueva Zelanda en función de la concentración que se administre de la misma, o dicho de otra forma, la curva dosis-respuesta de agomelatina. Para presentar los datos se ha realizado un ajuste logarítmico del efecto a diferentes valores de concentración, con un valor de EC50= 6,93*10"11 M. Según la información que refleja la curva, se observa que para aquellas concentraciones para las que se obtienen resultados estadísticamente significativos, desde 10~9 hasta 10"4 M, se produce un efecto similar, en torno a un 20% de reducción de la presión intraocular, respecto de un control tratado con vehículo. Este efecto se produce entre 90 y 210 minutos tras la aplicación de agomelatina, con una duración de entre 300 y 360 minutos, siendo estadísticamente significativa para la bajada de presión. Modo de realización de la invención Figure 2: This graph shows how the effect of agomelatine in an albino rabbit in New Zealand varies depending on the concentration administered by it, or in other words, the dose-response curve of agomelatine. To present the data, a logarithmic adjustment of the effect has been made to different concentration values, with a value of EC 50 = 6.93 * 10 "11 M. According to the information that reflects the curve, it is observed that for those concentrations for that statistically significant results are obtained, from 10 ~ 9 to 10 "4 M, a similar effect is produced, around a 20% reduction in intraocular pressure, with respect to a vehicle-treated control. This effect occurs between 90 and 210 minutes after the application of agomelatine, with a duration of between 300 and 360 minutes, being statistically significant for the pressure drop. Embodiment of the invention
Ejemplo 1 :  Example 1 :
A. Preparación de la formulación farmacéutica a administrar: A. Preparation of the pharmaceutical formulation to be administered:
La formulación farmacéutica de agomelatina a administrar de la presente invención se preparó disolviendo 2433 g del compuesto en 1000 μΙ_ de dimetil sulfóxido (DMSO), preparándose una solución concentrada del principio activo (solución madre). Hubo de realizarse esta etapa previa ya que la agomelatina no es soluble en soluciones acuosas. 10 μΙ_ de esta solución concentrada se mezclaron con 990 μΐ_ de solución salina (NaCI 0,9 %), obteniéndose una solución final de concentración 100 μΜ, que constituiría la formulación farmacéutica final de agomelatina a administrar. The pharmaceutical formulation of agomelatine to be administered of the present invention was prepared by dissolving 2433 g of the compound in 1000 µΙ_dimethyl sulfoxide (DMSO), preparing a concentrated solution of the active ingredient (stock solution). This previous stage had to be carried out since agomelatine is not soluble in aqueous solutions. 10 μΙ_ of this concentrated solution was mixed with 990 μΐ_ of saline solution (0.9% NaCl), obtaining a final solution of 100 μΜ concentration, which would constitute the final pharmaceutical formulation of agomelatine to be administered.
En la siguiente tabla se detalla la composición de la formulación final de agomelatina empleada en el ensayo: The following table details the composition of the final agomelatine formulation used in the test:
Figure imgf000012_0001
Figure imgf000012_0001
B. Diseño y realización del ensayo: B. Design and conduct of the test:
Se diseñó un ensayo específico para evaluar la seguridad y eficacia de la agomelatina como agente reductor de la presión intraocular. El ensayo diseñado comprendía tres etapas principales:  A specific trial was designed to evaluate the safety and efficacy of agomelatine as an intraocular pressure reducing agent. The designed trial comprised three main stages:
Etapa a: en primer lugar, medición de la presión intraocular de la especie animal elegida para el ensayo,  Stage a: first, measurement of the intraocular pressure of the animal species chosen for the test,
Etapa b: en segundo lugar, preparación de una formulación farmacéutica de agomelatina y administración de la misma a la especie animal en cuestión, Etapa c: en tercer lugar, y una vez administrada la composición farmacéutica, medición de la presión intraocular cada cierto tiempo para observar su variación a lo largo del tiempo. Stage b: secondly, preparation of a pharmaceutical formulation of agomelatine and administration thereof to the animal species in question, Stage c: thirdly, and once the pharmaceutical composition is administered, measurement of intraocular pressure from time to time to observe its variation over time.
Una vez diseñado el ensayo, y teniendo en cuenta que la presión intraocular tiene un valor característico y diferente según la especie animal y la raza de la que se trate, se escogió como modelo experimental para la realización del ensayo al conejo albino de Nueva Zelanda. Se utilizó una muestra de 7 conejos normotensos (la presión intraocular normal establecida para esta especie animal oscila entre 9,0 y 10,0 mm Hg) de los cuales uno de ellos fue asignado aleatoriamente al grupo control y el resto fueron asignados al grupo de tratamiento. Once the trial was designed, and taking into account that the intraocular pressure has a characteristic and different value depending on the animal species and the breed in question, the experimental model for the albino rabbit test in New Zealand was chosen as the experimental model. A sample of 7 normotensive rabbits was used (the normal intraocular pressure established for this animal species ranges between 9.0 and 10.0 mm Hg) of which one of them was randomly assigned to the control group and the rest were assigned to the group of treatment.
Etapa a: En todos los conejos se realizaron dos tipos de mediciones de presión intraocular antes de la administración de la formulación farmacéutica de agomelatina. La primera medición tuvo lugar 30 minutos antes del momento de la administración (t=-30), y la segunda, justo en el instante previo al momento de la administración (t=0). Para medir los valores de presión intraocular se usó un tonómetro de contacto (TonoVet®, Tiolat Oy). La media aritmética entre el valor de presión intraocular tomado en el conejo control 30 minutos antes de la administración de la formulación farmacéutica (constituida en el caso del conejo control solo por vehículo, sin la presencia de agomelatina) (t=-30) y el valor de presión intraocular recogido en el conejo control justo antes de administrar dicha formulación farmacéutica (t=0) se estableció como valor de referencia y se le asignó el valor de 100% de presión intraocular. El resto de los valores medidos tanto en el conejo control como en los conejos del grupo de tratamiento se normalizaron respecto a ese valor del 100%. Stage a: In all rabbits, two types of intraocular pressure measurements were performed before the administration of the pharmaceutical formulation of agomelatine. The first measurement took place 30 minutes before the time of administration (t = -30), and the second, just at the time before administration (t = 0). A contact tonometer (TonoVet®, Tiolat Oy) was used to measure intraocular pressure values. The arithmetic mean between the intraocular pressure value taken in the control rabbit 30 minutes before the administration of the pharmaceutical formulation (constituted in the case of the control rabbit only per vehicle, without the presence of agomelatine) (t = -30) and the Intraocular pressure value collected in the control rabbit just before administering said pharmaceutical formulation (t = 0) was established as a reference value and assigned the 100% intraocular pressure value. The rest of the values measured in both the control rabbit and the rabbits in the treatment group were normalized with respect to that value of 100%.
Etapa b: Se administró por vía tópica ocular a cada conejo del grupo de tratamiento 10 μί de la formulación final de agomelatina preparada siguiendo el procedimiento descrito en el apartado A de esta sección en forma de gotas. Al conejo control se le administró por vía tópica ocular 10 μί de una formulación farmacéutica de composición exactamente igual a la que se administró a los demás, con la única diferencia de que se excluyó la adición de agomelatina, es decir, la formulación farmacéutica se preparó mezclando 990 μΙ_ de solución salina (NaCI 0,9%) con 10 pL de DMSO para obtener una solución salina con 1% de DMSO, de la cual se tomaron 10 pL para su aplicación en el ojo del conejo. Stage b: Each rabbit in the treatment group 10 µί of the final formulation of agomelatine prepared by following the procedure described in section A of this section in the form of drops was administered topically. The control rabbit was administered 10 μί topically by ocular route of a pharmaceutical formulation of exactly the same composition as the one administered to the In addition, with the only difference that the addition of agomelatine was excluded, that is, the pharmaceutical formulation was prepared by mixing 990 μΙ_ of saline (0.9% NaCl) with 10 pL of DMSO to obtain a saline solution with 1% of DMSO, of which 10 pL was taken for application in the rabbit's eye.
Etapa c: Una vez administrada la formulación farmacéutica a cada uno de los conejos se hizo un seguimiento exhaustivo del comportamiento de los mismos a lo largo del tiempo. Para ello se realizaron mediciones del valor de presión intraocuiar, cada treinta minutos durante la primera hora posterior a la instilación (t=30 y t=60), y cada hora a partir de la segunda hora (t=120, t=180, t=240, t=300, t=360...). Para medir los valores de presión intraocuiar se usó un tonómetro de contacto (TonoVet®, Tiolat Oy). Stage c: Once the pharmaceutical formulation was administered to each of the rabbits, their behavior was carefully monitored over time. For this, measurements of the intraocuitary pressure value were made, every thirty minutes during the first hour after instillation (t = 30 and t = 60), and every hour after the second hour (t = 120, t = 180, t = 240, t = 300, t = 360 ...). A contact tonometer (TonoVet ® , Tiolat Oy) was used to measure intraocuitary pressure values.
El efecto de la agomelatina se estudió en términos de % de presión intraocuiar alcanzado respecto al valor de referencia (100%) en cada uno de los instantes en que se realizó una medición de presión intraocuiar. The effect of agomelatine was studied in terms of% of intra-cutaneous pressure reached with respect to the reference value (100%) in each of the moments in which an intra-cucumber pressure measurement was made.
Para obtener información sobre la farmacodinamia de la agomelatina se repitió el ensayo para distintas concentraciones de agomelatina en la formulación farmacéutica a administrar. To obtain information on the pharmacodynamics of agomelatine, the test was repeated for different concentrations of agomelatine in the pharmaceutical formulation to be administered.
En cada uno de los conejos del grupo de tratamiento se realizó cada ensayo tres veces en tres semanas consecutivas, dejando un periodo de tiempo de una semana entre ensayo y ensayo para que el conejo recuperara el valor inicial de presión intraocuiar de forma que las condiciones iniciales en esos tres ensayos fueran las mismas. La formulación farmacéutica de agomelatina se administró a los seis conejos de forma sucesiva y respetando siempre el mismo orden de administración. Cada una de las mediciones de la presión intraocuiar se realizó por triplicado estableciendo como valor final la media de esos tres valores. In each of the rabbits of the treatment group, each trial was performed three times in three consecutive weeks, leaving a period of one week between trial and trial for the rabbit to recover the initial intraocular pressure value so that the initial conditions in those three essays they were the same. The pharmaceutical formulation of agomelatine was administered to the six rabbits in succession and always respecting the same order of administration. Each of the intraocuous pressure measurements was performed in triplicate, establishing as a final value the average of these three values.
En la Figura 1 se presenta una comparativa de la evolución del valor de la presión intraocuiar (PIO) entre el grupo de control y el grupo de tratamiento, desde media hora antes de la administración de la formulación farmacéutica hasta seis horas después de la administración. Según la gráfica, la administración de agomelatina en un conejo albino de Nueva Zelanda proporciona una reducción de la presión intraocular del 21% a los 180 minutos de la administración, volviendo a recuperar el valor inicial de presión intraocular a los 360 minutos de la administración de la formulación. Figure 1 shows a comparison of the evolution of the value of intraocuitary pressure (IOP) between the control group and the treatment group, from half an hour before the administration of the pharmaceutical formulation to six hours. after administration According to the graph, the administration of agomelatine in an albino rabbit from New Zealand provides a reduction of intraocular pressure of 21% at 180 minutes after administration, returning to recover the initial value of intraocular pressure at 360 minutes after administration of the formulation
El examen de los datos fue rigurosamente analizado estadísticamente y las diferencias se probaron por el test de la t de student, considerando como diferencias significativas aquellos valores en donde p<0,05 con respecto al valor control. Los resultados presentados en la Figura 1 son la media ± s.e.m. (error estándar de la media) de 18 experimentos independientes, que son los tres ensayos llevados a cabo con la formulación preparada en el apartado A de esta sección -con una concentración de agomelatina de concentración 100 μΜ- en los seis conejos del grupo de tratamiento. The examination of the data was rigorously analyzed statistically and the differences were tested by the student t test, considering as significant differences those values where p <0.05 with respect to the control value. The results presented in Figure 1 are the mean ± s.e.m. (standard error of the mean) of 18 independent experiments, which are the three tests carried out with the formulation prepared in section A of this section - with an agomelatine concentration of 100 μΜ concentration - in the six rabbits of the treatment group .
La información sobre la farmacodinamia de la agomelatina se completó mediante la construcción de la curva dosis-respuesta (Figura 2) que proporciona información sobre el efecto de la agomelatina en un conejo albino de Nueva Zelanda en función de la concentración que se administre de la misma. Para la elaboración de dicha curva se administró a los conejos distintas concentraciones del principio activo y se estudió el efecto -en términos de % de presión intraocular alcanzado respecto al valor de referencia (100%)- de cada una de dichas concentraciones en los conejos. La información proporcionada por esta curva permite determinar la dosis efectiva y la forma correcta de administración del fármaco en la especie animal concreta sobre la que se está trabajando. Information on the pharmacodynamics of agomelatine was completed by constructing the dose-response curve (Figure 2) that provides information on the effect of agomelatine on an albino rabbit in New Zealand based on the concentration administered from it. . For the elaboration of this curve, different concentrations of the active substance were administered to rabbits and the effect was studied - in terms of% of intraocular pressure reached with respect to the reference value (100%) - of each of said concentrations in rabbits. The information provided by this curve allows to determine the effective dose and the correct form of administration of the drug in the specific animal species on which it is working.
Para presentar los datos se ha realizado un ajuste logarítmico del efecto a diferentes valores de concentración, con un valor de EC50= 6,93*10"11 M. Al igual que en la curva anterior, el examen de los datos fue rigurosamente analizado estadísticamente y las diferencias se probaron por el test de la t de student, considerando como diferencias significativas aquellos valores en donde p<0,05 con respecto al valor control. Según la información que refleja la curva, se observa que para concentraciones inferiores a 10"9 M los resultados no son estadísticamente significativos y por ello no se tienen en cuenta. Para concentraciones desde 10'9 hasta 10" M se produjo un efecto similar, en torno a un 20% de reducción de la presión intraocular, respecto de un control tratado con vehículo. Este efecto se produjo entre 90 y 210 minutos tras la aplicación de agomelatina, con una duración de entre 300 y 360 minutos, siendo estadísticamente significativa para la bajada de presión. To present the data, a logarithmic adjustment of the effect has been made to different concentration values, with a value of EC 50 = 6.93 * 10 "11 M. As in the previous curve, the examination of the data was rigorously analyzed. statistically and the differences were tested by the student t test, considering as significant differences those values where p <0.05 with respect to the control value.According to the information that reflects the curve, it is observed that for concentrations below 10 "9 M the results are not statistically significant and therefore are not taken into account. For concentrations from 10 '9 to 10 " M a similar effect occurred, around a 20% reduction in intraocular pressure, compared to a vehicle-treated control. This effect occurred between 90 and 210 minutes after the application of agomelatine, with a duration of between 300 and 360 minutes, being statistically significant for the pressure drop.
A partir de todos los datos recogidos en el ensayo se concluye que la administración por vía tópica ocular en un conejo albino de Nueva Zelanda de una formulación farmacéutica con una concentración de agomelatina dentro del intervalo entre 10"9 y 10"4 M es capaz de producir una reducción de la presión intraocular de hasta el 21%, requiriendo para ello un periodo de tiempo que varía entre 90 y 210 minutos tras la administración de la formulación, y volviendo a recuperar el valor inicial de presión intraocular a los 360 minutos de la administración de la formulación. From all the data collected in the trial it is concluded that administration by topical ocular route in a New Zealand albino rabbit of a pharmaceutical formulation with a concentration of agomelatine within the range between 10 "9 and 10 " 4 M is capable of produce a reduction in intraocular pressure of up to 21%, requiring a period of time that varies between 90 and 210 minutes after administration of the formulation, and returning to recover the initial value of intraocular pressure 360 minutes after formulation administration.

Claims

Reivindicaciones Claims
1. Uso del compuesto N-[2-(7-metoxinaftalen-1-il)etil]acetam¡da, también llamado agomelatina, de la fórmula I)  1. Use of the compound N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, also called agomelatine, of the formula I)
Figure imgf000017_0001
Figure imgf000017_0001
(I) y/o sales farmacéuticamente aceptables de la misma para la preparación de un medicamento destinado a la reducción de la presión intraocular.  (I) and / or pharmaceutically acceptable salts thereof for the preparation of a medicament intended for the reduction of intraocular pressure.
2. Uso según la reivindicación 1 para el tratamiento y/o prevención del glaucoma hipertenso o normotenso y/o enfermedades caracterizadas por una elevada presión intraocular. 2. Use according to claim 1 for the treatment and / or prevention of hypertensive or normotensive glaucoma and / or diseases characterized by high intraocular pressure.
3. Uso según la reivindicación 2 en el que las enfermedades caracterizadas por una elevada presión intraocular se seleccionan del grupo comprendido por infecciones oculares, inflamaciones oculares, uveítis y retinopatía diabética. 3. Use according to claim 2 wherein the diseases characterized by high intraocular pressure are selected from the group comprised of ocular infections, ocular inflammations, uveitis and diabetic retinopathy.
4. Uso según las reivindicaciones 1-3, en el que el medicamento se administra en una cantidad profiláctica y/o terapéutica eficaz y está adaptado para su administración por una vía seleccionada del grupo comprendido por las vías tópica, oral, sublingual, rectal, intradérmica, subcutánea, intramuscular, endovenosa, intracardíaca, intraraquídea, intraarticular, percutánea o transdérmica, e inhalada. 4. Use according to claims 1-3, wherein the medicament is administered in an effective prophylactic and / or therapeutic amount and is adapted for administration by a route selected from the group comprised by the topical, oral, sublingual, rectal routes, intradermal, subcutaneous, intramuscular, endovenous, intracardiac, intrarachial, intraarticular, percutaneous or transdermal, and inhaled.
5. Uso según la reivindicación 4, en el que el medicamento se administra por vía tópica, estando el compuesto vehiculizado o no mediante liposomas, y presenta una forma farmacéutica seleccionada del grupo comprendido por soluciones, suspensiones, emulsiones, colirios, gotas de líquido, lavados de líquido cremas, ungüentos, pomadas y sprays. 5. Use according to claim 4, wherein the medicament is administered topically, whether or not the compound is vehicularized by liposomes, and has a pharmaceutical form selected from the group comprised of solutions, suspensions, emulsions, eye drops, liquid drops, liquid washing creams, ointments, ointments and sprays.
PCT/ES2012/000264 2011-10-28 2012-10-11 Use of a melatonin analogue for the reduction of intraocular pressure WO2013060908A1 (en)

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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AGORASTOS A. ET AL: "The role of melatonin in glaucoma: implications concerning pathophysiological relevance and therapeutic potential", J. PINEAL RES., vol. 50, 2011, pages 1 - 7, XP055065950 *
CROOKE A. ET AL: "Update in glaucoma medicinal chemistry: Emerging evidence for the importance of melatonin analogues", CURRENT MEDICINAL CHEMISTRY, vol. 19, July 2012 (2012-07-01), pages 3508 - 3522, XP055065960 *
SEITHIKURIPPU R. PANDI-PERUMAL ET AL: "Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways", PROGRESS IN NEUROBIOLOGY, vol. 85, 2008, pages 335 - 353, XP022824509 *

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