• 专利附录
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    • 专利摘要:
    Use of melatoninergic compounds to treat the ocular surface. Increase in tear secretion and/or improve the quality of the tear film by means of melatonin analogs such as agomelatine, 5-mca-nat and/or iik7. The present invention describes a method for increasing lacrimal secretion and/or improving the quality of the tear film by administering a pharmaceutical formulation of the substance agomelatine (N- [2- (7-methoxynaphthalen-1-yl) ethyl) acetamide), 5-mca-nat (5-methoxycarbonylamino-N-acetyltriptamine) and/or iik7 (N-butanoyl 2- (9-methoxy-6h-iso-indolo [2,1-a] indol-11-yl) ) -etanamine)) and/or pharmaceutically acceptable salts thereof. In the present invention, the use of agomelatine, 5-mca-nat and/or iik7 and/or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment and/or prevention of dry eye and/or diseases characterized by a decrease in lacrimal secretion and/or poor quality of the tear film. Said medicament is preferably administered topically, whether or not it is transported by liposomes, and it can be presented in different pharmaceutical forms, such as solutions, suspensions, emulsions, eye drops, liquid drops, liquid washes, contact lenses, gels, creams, ointments., ointments and sprays. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2597827A1
    申请号:ES201500545
    申请日:2015-07-21
    公开日:2017-01-23
    发明作者:Alejandro MARTÍNEZ AGUILAR；Begoña FONSECA VÁZQUEZ；Juan Gonzalo CARRACEDO RODRÍGUEZ；Jesús PINTOR JUST
    申请人:Ocupharm Diagnostics Sl；
    IPC主号:
    专利说明:

    as "poor tear film quality" and also as "suspicion of dry eye". Dry eye is a very prevalent disease affecting between 14 and 33% of the world's population, depending on the study and the definition used (Messmer EM. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch Arztebl Int. 112 (5): 71-81 (2015)).
    The classification of the dry eye is based on two blocks: from an etiological perspective and from the influence of the environment, which predisposes to the development of dry eye. The etiological classification in turn is subdivided into two main groups: Dry eye due to deficiency in the aqueous phase of the tear, and evaporative dry eye. However, these groups are not independent, since the disease initiated in one of the main groups can coexist with circumstances that cause dry eye within the other group (Lemp MA. Management of dry eye disease. Am J Manag Careo 14 (3 Suppl ): S88-101 (2008)).
    Current treatment options for dry eye are tear supplements, also called lubricants, known as artificial rhymes. The effectiveness of this option is difficult to verify, because its effects cannot be observed or because the currently available agents do not have a discernible activity of the lubrication effect. An improvement in the symptoms can be observed, but it is not enough to resolve the pathology on the ocular surface or the inflammation that they present on the ocular surface (Moshirfar M, Pierson K, Hanamaikai K, Santiago Caban L, Muthappan V, Passi SF. Artificial tears potpourri: a literature review Clin Ophthalmol. 31; 8: 1419-1433 (2014)).
    Other treatment options are anti-inflammatory medications such as cyclosporine, corticosteroids, tetracyclines and the like; tear retention devices, such as permanent occlusion plugs of the tear duct; moisture glasses; contact lenses; and tear gland autotransplantation. However, none of these treatments is free of unwanted side effects (Colligris B, Crooke A, Huete-Toral F, Painter J. An update on dry eye disease molecular treatment: advances in drug pipelines. Expert Opin Pharmacother. 15 (10 ): 1371-1390 (2014)).
    In the search for new, more effective substances with fewer side effects for the treatment of dry eye, 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 linked to a significant number of aspects of medical research (Reiter RJ, Tan DX, Galano
    A. Melatonin: exceeding expectations. Physiology (Bethesda). 29 (5): 325-333 (2014)). The treatment of Parkinson's disease, epilepsy or other behavioral disorders demonstrates the pharmacological potential of this substance. For example, the patent, U.S. Pat. No. 3,642,994 describes the symptomatic treatment of said diseases by means of oral or parenteral administration of melatonin.
    Treatment with melatonin of different pathologies in different experimental models has revealed the presence of this neurohormone in the intraocular space, however in the scientific literature it has been possible to demonstrate that melatonin has no effect on tear secretion per se which does not make it attractive in principle for the treatment of dry eyes (Hoyle CH, Peral A, Painter
    J. Melatonin potentiates tear secretion induced by diadenosine tetraphosphate in the rabbit. Eur J Pharmacol. 552 (1-3): 159-161 (2006)).
    On the other hand, agomelatine is an analogue of melatonin and a potent agonist of MT1 and MT2 melatonin receptors and, with a lower affinity, antagonizes 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, a or 13, cholinergic receptors, or for dopamine receptors. This melatonin analog is currently used as an 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. Explanation of the invention.
    In the present invention a method for increasing tear secretion and / or improving the quality of the tear film in a subject comprising the administration of melatonin analogues (agomelatine, 5-MCA-NAT and / or IIK7) and / or is described pharmaceutically acceptable salts thereof. The invention also relates to the treatment and / or prevention of dry eye and / or diseases characterized by a decrease in tear secretion and / or by poor quality of the tear film, by administering a quantity of and / or analogues of melatonin (agomelatine, 5-MCA-NAT and / or IIK7) and / or pharmaceutically acceptable salts thereof, which is effective in increasing tear secretion, in a patient, at levels where disease progression stops or disappears the signs and / or symptoms.
    In the present invention, the term "dry eye" refers to that eye with deteriorated ocular surface, tear film instability, low tear, high osmolarity, low values of mucins and lysozyme and / or with symptoms such as discomfort, itching, dryness and / or feeling of sand.
    In the present invention, the terms "subject" or "patient" are equivalent and interchangeable and refer to any animal species that is capable of presenting a tear secretion value and / or osmolarity lower than the normal values established for that animal species and race in question, and / or be susceptible to dry eye - in any of its varieties - and / or any disease characterized by a decrease in tear secretion and / or poor quality of the tear film. Examples of animal species included within the scope of these expressions are the human being, mouse, rabbit, dog, cat and horse among others.
    It should be borne in mind that the use in this description and in the claims of the articles el / la, a / ato includes the reference to the plural unless otherwise explicitly stated in the context.
    The present report claims a method to increase tear secretion and / or improve the quality of the tear film in a subject. Another aspect of the invention claims a method for treating and / or preventing dry eye and / or diseases characterized by a decrease in tear secretion and / or poor quality.
    of the tear film, in a patient. More particularly, the present specification refers to a method to increase tear secretion and / or improve tear film quality using agomelatine (N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide), 5-MCA-NAT (5-Methoxycarbonylamino-N-acetyltriptamine) and / or IIK7 (N-Butanoyl 2- (9-methoxy5 6H-iso-indole [2, 1-a] indole-11-yl) -etanamine), and / or pharmaceutically acceptable salts thereof, in a subject. Another aspect of the present report refers to a method for treating and / or preventing dry eye and / or diseases characterized by a decrease in tear secretion and / or by poor quality of the tear film characterized by a decrease in secretion. tear and / or poor quality of the
    10 tear film using agomelatine (N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide), 5-MCA-NAT (5-Methoxycarbonylamino-N-acetyltriptamine) and / or IIK7 (N-Butanoyl 2- ( 9-methoxy6H-iso-indole [2,1-a] indole-11-yl) -ethanamine), and / or pharmaceutically acceptable salts thereof, in a patient.
    The present invention is described as a method to increase tear secretion and / or improve the quality of the tear film, through the application of agomelatine (N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide ), 5-MCA-NAT (5Methoxycarbonylamino-N-acetyltriptamine) and / or IIK7 (N-Butanoyl 2- (9-methoxy-6Hiso-indole [2, 1-a] indole-11-yl) -etanamine), and / or pharmaceutically acceptable salts of the
    The same, as well as the methods of using said compounds in the dry eye and / or diseases characterized by a decrease in tear secretion and / or by a poor quality of the tear film.
    The substances referred to in the present invention, agomelatine (N
    25 [2- (7-Methoxynaphthalen-1-yl) ethyl] acetamide), 5-MCA-NAT (5-Methoxycarbonylamino-Nacetyltriptamine) and / or IIK7 (N-Butanoyl 2- (9-methoxy-6H-iso-indole) [2,1-a] indole-11yl) -ethanamine), are described by the following formulas (1-111):
    (1) Agomelatine
    CH3
    I
    0yN
    °
    (11) 5-MCA-NAT
    H N ~ CH3
    H ~ O
    OR
    (1II) IIK7
    The agomelatine compound, N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, is characterized by specifically binding to MT1 and MT2 type melatonin receptors
    10 (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 MT1 and MT2 receptors Naunyn Schmiedebergs Arch. Pharmacol. 367, 553-561.).
    The compound 5-Methoxycarbonylamino-N-acetyltriptamine, also called 5-MCA-NAT, is characterized by binding to the tentatively named MT3 receptors, through which, together with the MT2, they mediate their physiological and pharmacological actions (Alarm- Estrany P, Painter J. Melatonin receptors in the eye: location, second
    20 messengers and role in ocular physiology. Pharmacol Ther. 2007 Mar; 113 (3): 507-22.
    The compound N-Butanoyl 2- (9-methoxy-6H-iso-indole [2,1-a] indole-11-yl) -etanamine, also called IIK7, is characterized by more selectively binding to MT2 receptors of melatonin (Alarma-Estrany P, Crooke A, Mediero A, Peláez T,
    25 Painter J. Sympathetic nervous system modulates the ocular hypotensive action of MT2melatonin receptors in normotensive rabbits. J Pineal Res. 2008 Nov; 45 (4): 468-75).
    Various pharmaceutical formulations of agomelatine (N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide), 5-MCA-NAT (5Methoxycarbonylamino-N-acetyltriptamine) and / or IIK7 (N-) are claimed herein. Butanoyl 2- (9-methoxy-6Hiso-indole [2,1-a] indole-11-yl) -etanamine), and / or pharmaceutically acceptable salts thereof for use in increasing tear secretion as well as in the treatment and / or prevention of dry eye and / or diseases characterized by having associated dry eye and / or poor quality of the tear film, in a patient. More particularly, diseases characterized by having a dry eye are selected from the group included among others by Sj6gren's syndrome, aniridia, rheumatoid arthritis, lupus, sarcoidosis, allergies and skin diseases or eventual situations such as menopause or as a consequence of situations environmental conditions such as very low humidity conditions, high temperatures, heating devices or air conditioners. Similarly, some pharmacological and / or surgical treatments can lead to dry eyes, such as the use of decongestants and antihistamines, tranquilizers, antidepressants and sleeping pills, diuretics, birth control pills, some anesthetics, medications for the treatment of high blood pressure (beta blockers) and for digestive disorders (anticholinergics) or refractive surgery operations.
    Another aspect of the present specification refers to the fact that the medicaments of the present invention are administered in an effective prophylactic and / or therapeutic amount and are adapted for administration by a route selected from the group comprised by the topical routes, contact lenses. , oral, intracamerular, intravitreal, sublingual, rectal, intradermal, subcutaneous, intramuscular, intravenous, intracardiac, intraracheal, intraarticular, percutaneous or transdermal, and inhaled or by means of ocular regulated release devices.
    In an embodiment of the present invention, the medicament is administered topically, the compound being vehiculized or not by liposomes, and has a pharmaceutical form selected from the group comprised of solutions, suspensions, emulsions, eye drops, liquid drops, washes of liquid, contact lenses, gels, creams, ointments, ointments and sprays.
    Another aspect of the invention relates to an assay specifically designed to demonstrate the efficacy of agomelatine (N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide), 5-MCA-NAT (5-Methoxycarbonylamino-N -acetyltriptamine) and / or IIK7 (N-Butanoyl 2- (9-methoxy6H-iso-indole [2,1-a] indole-11-yl) -ethanamine), and / or pharmaceutically acceptable salts thereof in the increment of tear secretion and / or improvement of the quality of
    tear film in a subject Consequently, the described efficacy also demonstrates the efficacy of agomelatine, 5-MCA-NAT, and / or IIK7 and / or pharmaceutically acceptable salts thereof in the treatment and / or prevention of dry eye. and / or diseases characterized by having dry eye associated.
    The essay comprises three main stages. First, the tear secretion of the animal species chosen for the test is measured. Secondly, a pharmaceutical formulation of agomelatine, 5-MCA-NAT, and / or IIK7 and / or pharmaceutically acceptable salts thereof is prepared and administered to the animal species in question. Thirdly, and once the pharmaceutical composition is administered, tear secretion is measured from time to time to observe its variation over time.
    From the data obtained with the different measurements it is possible to construct the curve that shows the effect of the active principle over time. Through this curve it is possible to determine how the effect of the active principle varies over time, as well as the maximum effect they reach.
    More specifically, from the data collected in the trial, information can be obtained on what is the increase in tear secretion obtained with respect to the initial value, how long it takes to reach that maximum value of tear secretion, for how long it is maintained that value of tear secretion reached and from what moment the tear secretion begins to return to basal values.
    More particularly, the New Zealand albino rabbit was chosen for the test as an experimental model and the tear secretion of its eyes was measured before and after the administration of the pharmaceutical formulation of agomelatine, 5-MCANAT, and / or IIK7 prepared .
    Description of the figures Figure 1: This graph presents a comparison of the evolution of tear secretion between the control group and the treatment groups, from just before administration of the pharmaceutical formulation to three hours after administration. According to the information provided by the graph, the administration of agomelatine, 5-MCA-NAT and IIK7 in an albino rabbit from New Zealand following the procedure described in examples 1! 2 and 3, respectively, of the section "Embodiment of the invention" are capable of achieving an increase in the
    tear secretion of 28.3%, 27.7% and 27.9% respectively, 60 minutes after administration, remaining elevated from 30 to 180 minutes.
    Figure 2: This graph shows the maximum effect of agomelatine, 5-MCA-NAT and IIK7 on an albino rabbit from New Zealand. This effect occurs at 60 minutes after the application of agomelatine, 5-MCA-NAT and IIK7, with a duration of about 150 minutes, being statistically significant for the increase of tear secretion.
    Embodiment of the invention
    Example 1:
    A. Preparation of the pharmaceutical formulation to be administered:
    The pharmaceutical formulation of agomelatine to be administered of the present invention was prepared by dissolving 2433 IJg of the compound in 1000 IJL of 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 IJL of this concentrated solution was mixed with 990 IJL of saline solution (0.9% NaCl), obtaining a final solution of 100 IJM concentration, which would constitute the final pharmaceutical formulation of agomelatine to be administered.
    The following table details the composition of the final agomelatine formulation used in the test:
    Ingredient Quantity
    Agomelatine 10 IJL of the 10 mM stock solution (prepared in DMSO)
    Saline solution (0.9% NaCl) 990 IJL
    B. Design and conduct of the test:
    A specific trial was designed to evaluate the safety and efficacy of agomelatine as a stimulating agent for tear secretion. The designed trial comprised three main stages:
    Stage a: first, measurement of tear secretion of the animal species
    chosen for the essay,
    Stage b: second, 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 tear secretion from time to time to observe its variation at
    the long of the time.
    Once the trial was designed, and taking into account that the tear secretion has a characteristic and different value depending on the animal species and the breed in question, it was chosen as an experimental model for the test of the albino rabbit in New Zealand. A sample of 12 rabbits was used, of which six of them were randomly assigned to the control group and the rest were assigned to the treatment group.
    Stage a: In all rabbits, a tear secretion measurement was performed before the administration of the pharmaceutical formulation of agomelatine. The measurement took place just before the time of administration (t = O). To measure tear secretion values, strips of schirmer tear flo HUB pharmaceuticals LLC were used.
    At the baseline value obtained before the administration of the pharmaceutical formulation (constituted in the case of the control rabbit only per vehicle, without the presence of agomelatine) collected in the control rabbit just before administering said pharmaceutical formulation (t = O) it was established as reference value and 100% tear secretion value was assigned. 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 10 IJL treatment group of the final agomelatine formulation prepared by following the procedure described in section A of this section as drops was administered topically. The control rabbit was given topical ocular route 10 IJL of a pharmaceutical formulation of exactly the same composition as the one administered to the others, with the only difference that the addition of agomelatine was excluded, that is, the pharmaceutical formulation was prepared mixing 990 IJL of saline solution (0.9% NaCl) with 10 IJL of DMSO to obtain a saline solution with 1% DMSO, from which 10 IJL was taken for application in the rabbit's eye.
    Stage c: Once the pharmaceutical formulation was administered to each of the rabbits, their behavior was carefully monitored over time. For this, measurements of tear secretion were made, every thirty minutes during the first hour after instillation (t = 30 and t = 60) and then every sixty minutes until 3 hours (t = 120 and t = 180). To measure tear secretion values, schirmer tear flo HUB pharmaceuticals LLC strips were used
    Example 2:
    A. Preparation of the pharmaceutical formulation to be administered:
    The pharmaceutical formulation of 5-MCA-NAT to be administered of the present invention was prepared by dissolving 2753 IJg of the compound in 1000 IJL of dimethyl sulfoxide (DMSO), preparing a concentrated solution of the active ingredient (stock solution). This previous stage had to be carried out since 5-MCA-NAT is not soluble in aqueous solutions. 10 IJL of this concentrated solution was mixed with 990 IJL of saline solution (0.9% NaCl), obtaining a final solution of 100 IJM concentration, which would constitute the final pharmaceutical formulation of 5-MCA-NAT to be administered.
    The following table details the composition of the final 5-MCA-NAT formulation used in the test:
    Ingredient Quantity
    5-MCA-NAT 10 IJL of the 10 mM stock solution (prepared in DMSO)
    Saline solution (0.9% NaCl) 990 IJL
    B. Design and conduct of the test:A specific trial was designed to evaluate the safety and efficacy of 5-MCA-NATas a stimulating agent for tear secretion. The designed trial includedthree main stages:
    Stage a: first, measurement of tear secretion of the animal specieschosen for the essay,Stage b: second, preparation of a pharmaceutical formulation of 5-MCA-NAT and its administration to the animal species in question,Stage c: thirdly, and once the pharmaceutical composition is administered,measurement of tear secretion from time to time to observe its variation atthe long of the time.
    Once the trial was designed, and taking into account that the tear secretion has a characteristic and different value depending on the animal species and the breed in question, it was chosen as an experimental model for the test of the albino rabbit in New Zealand. A sample of 12 rabbits was used, of which six of them were randomly assigned to the control group and the rest were assigned to the treatment group.
    Stage a: In all rabbits a tear secretion measurement was performed before administration of the 5-MCA-NA T pharmaceutical formulation. The measurement took place just before the time of administration (t = O). To measure tear secretion values, strips of schirmer tear flo HUB pharmaceuticals LLC were used.
    The baseline value obtained before the administration of the pharmaceutical formulation (constituted in the case of the control rabbit only per vehicle, without the presence of 5-MCANAT) collected in the control rabbit just before administering said pharmaceutical formulation (t = O) is established as a reference value and assigned 100% tear secretion 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%.
    Stage b: Each rabbit in the 10 IJL treatment group of the final 5-MCA-NAT formulation prepared following the procedure described in section A of this section as drops was administered topically. The control rabbit was given topical ocular route 10 IJL of a pharmaceutical formulation of exactly the same composition as the one administered to the others, with the only difference that the addition of 5-MCA-NAT was excluded, that is, the Pharmaceutical formulation was prepared by mixing 990 IJL of saline solution (0.9% NaCl) with 10 IJL of DMSO to obtain a saline solution with 1% DMSO, from which 10 IJL was taken for application in the rabbit's eye.
    Stage c: Once the pharmaceutical formulation was administered to each of the rabbits, their behavior was carefully monitored over time. For this, measurements of tear secretion were made, every thirty minutes during the first hour after instillation (t = 30 and t = 60) and then every
    10 sixty minutes until 3 hours (t = 120 and t = 180). To measure tear secretion values, schirmer tear flo HUB pharmaceuticals LLC strips were used
    Example 3:
    15 A. Preparation of the pharmaceutical formulation to be administered:
    The pharmaceutical formulation of IIK7 to be administered of the present invention was prepared by dissolving 3484 IJg of the compound in 1000 IJL of dimethyl sulfoxide (DMSO), preparing a concentrated solution of the active ingredient (stock solution). There was
    This previous stage is carried out since IIK7 is not soluble in aqueous solutions. 10 IJL of this concentrated solution was mixed with 990 IJL of saline solution (0.9% NaCl), obtaining a final solution of 100 IJM concentration, which would constitute the final pharmaceutical formulation of IIK7 to be administered.
    25 The composition of the final formulation of IIK7 used in the test is detailed in the following table:
    Ingredient Quantity
    IIK7 10 IJL of the 10 mM stock solution (prepared in DMSO)
    Saline solution (0.9% NaCl) 990 IJL
    B. Design and conduct of the test:
    30 A specific trial was designed to evaluate the safety and efficacy of IIK7 as a stimulating agent for tear secretion. The designed trial comprised three
    main stages: Stage a: first, measurement of the tear secretion of the animal species chosen for the test, Stage b: secondly, preparation of a pharmaceutical formulation of IIK7 and administration thereof to the animal species in question, Stage c: thirdly, and once the pharmaceutical composition is administered, measurement of tear secretion from time to time to observe its variation over time.
    Once the trial was designed, and taking into account that the tear secretion has a characteristic and different value depending on the animal species and the breed in question, it was chosen as an experimental model for the test of the albino rabbit in New Zealand. A sample of 12 rabbits was used, of which six of them were randomly assigned to the control group and the rest were assigned to the treatment group.
    Stage a: In all rabbits a tear secretion measurement was performed before administration of the pharmaceutical formulation of IIK7. The measurement took place just before the time of administration (t = O). To measure tear secretion values, strips of schirmer tear flo HUB pharmaceuticals LLC were used.
    At the baseline value obtained before the administration of the pharmaceutical formulation (constituted in the case of the control rabbit only per vehicle, without the presence of IIK7) collected in the control rabbit just before administering said pharmaceutical formulation (t = O) it was established as reference value and 100% tear secretion value was assigned. 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 10 IJL treatment group of the final formulation of IIK7 prepared by following the procedure described in section A of this section as drops was administered topically. The control rabbit was given topical ocular route 10 IJL of a pharmaceutical formulation of exactly the same composition as the one administered to the others, with the only difference that the addition of IIK7 was excluded, that is, the pharmaceutical formulation was prepared mixing 990 IJL of saline solution (0.9% NaCl) with 10 IJL of DMSO to obtain a saline solution with 1% DMSO, from which 10 IJL was taken for application in the rabbit's eye.
    Stage c: Once the pharmaceutical formulation was administered to each of the rabbits, their behavior was carefully monitored over time. For this, measurements of tear secretion were made, every thirty minutes during the first hour after instillation (t = 30 and t = 60) and then every sixty minutes until 3 hours (t = 120 and t = 180). To measure tear secretion values, schirmer tear tia HUB pharmaceuticals LLC strips were used
    The effect of the compounds agomelatine, 5-MCA-NAT and IIK7 was studied in terms of% of tear secretion achieved with respect to the reference value (100%) in each of the moments in which a tear secretion measurement was made.
    In each of the rabbits in the treatment group, each trial was performed twice in two consecutive weeks, so that the initial conditions in those two trials were the same. The pharmaceutical formulation of agomelatine, 5-MCANAT and / or IIK7 was administered to the six rabbits in succession and always respecting the same order of administration.
    Figure 1 shows a comparison of the evolution of tear secretion between the control group and the treatment groups, from the administration of the pharmaceutical formulation to three hours after the administration. According to the graph, the administration of agomelatine, 5-MCA-NAT and IIK7 in an albino rabbit from New Zealand provides an increase in tear secretion of 28.3%, 27.7% and 27.9% respectively, at 60 minutes of administration, staying elevated from 30 to 180 minutes.
    The examination of the data was rigorously analyzed statistically and the differences were tested by the student's 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 12 independent experiments, which are the two tests carried out with the formulation prepared in section A of this section, with a concentration of agomelatine, 5-MCA-NAT and / or IIK7 of concentration 100 IJM, in the six rabbits of the treatment group.
    权利要求:
    Claims (6)
    [1]
     Claims
    1. Use of the compound N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, also called agomelatine, of the formula (1)
    (I)
    and / or pharmaceutically acceptable salts thereof for the preparation of a medicament intended to increase tear secretion.
    10 2. Use of the compound 5-Methoxycarbonylamino-N-acetyltriptamine, also called 5-MeA-NAT, of the formula (11)
    or
     N) lCH
    H 3
     (II)
    and / or pharmaceutically acceptable salts thereof for the preparation of a medicament intended to increase tear secretion.
    [3]
    3. Use of the compound N-Butanoyl 2- (9-methoxy-6H-iso-indole [2,1-a] indole-11yl) -ethanamine, also called IIK7, of the formula (111)
    (III)
    and / or pharmaceutically acceptable salts thereof for the preparation of a medicament intended to increase tear secretion.
    [4]
    Four. Use according to claims 1-3 for the treatment and / or prevention of dry eye and / or diseases characterized by running with dry eye and / or poor quality of the tear film.
    [5]
    5. Use according to claim 4 wherein the diseases characterized by having a dry eye are selected from the group comprised of Sjogren's syndrome, aniridia, rheumatoid arthritis, lupus, sarcoidosis, allergies and skin diseases or eventual situations such as menopause or as a consequence of environmental situations such as very low humidity conditions, high temperatures, heating devices or air conditioners. Similarly, some pharmacological and / or surgical treatments can lead to dry eyes, such as the use of decongestants and antihistamines, tranquilizers, antidepressants and sleeping pills, diuretics, birth control pills, some anesthetics, medications for the treatment of hypertension (beta blockers) and for digestive disorders (anticholinergics) or refractive surgery operations.
    [6]
    6. Use according to claims 1-5, 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 routes, contact lenses, oral, intracamerular, intravitrea, sublingual, rectal, intradermal, subcutaneous, intramuscular, endovenous, intracardiac, intrarachial, intraarticular, percutaneous or transdermal, and inhaled or by means of ocular devices with regulated release.
    [7]
    7. Use according to claim 6, wherein the medicament is administered topically, whether or not the compound is vehicularized by liposomes, and has a pharmaceutical form selected from the group comprising solutions, suspensions, emulsions, eye drops, liquid drops, washings of liquid, contact lenses, gels, creams, ointments, ointments and sprays.
    Figure 1
    .-.
    and
    --- Basal
    - + -Agomelatine
    --5-MCA-NAT
    - + -IIK7
    1 !! 90 ~ --- "'T"' "" --- r -----.
    lil o 60 120 180
    (f) Time (mln)
    Figure 2
    类似技术:
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    ES2543974T3|2015-08-26|Ophthalmic compositions and methods to treat the eyes
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    IT201900002913A1|2019-03-01|2020-09-01|Nicola Pescosolido|Compound useful for the treatment of glaucoma|
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