ES2947238A1 - OLIVE OIL FOR USE AS AN OCULAR HYPOTENSOR (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Wild olive oil for use as an ocular hypotensive. The present invention refers to olive oil (fruit of the wild olive or wild olive tree, Olea europea L. var. sylvestris or oleaster) for use in the prevention and treatment of ocular hypertension and ocular pathologies that are favored by high levels of intraocular pressure such as uveitis, high myopia and keratoconus, as well as food and pharmaceutical compositions that comprise it. (Machine-translation by Google Translate, not legally binding)

Description

DESCRIPTION

Olive oil for use as an ocular hypotensive agent

The present invention is within the field of Medicine and Nutrition. The present invention refers to the use of olive oil (fruit of the wild olive tree, Olea europea L. var. sylvestris or oleaster) as a hypotensive agent in the prevention and treatment of ocular hypertension and ocular pathologies that are favored by high levels. of intraocular pressure such as keratoconus, uveitis and high myopia, as well as food and pharmaceutical compositions that include it.

BACKGROUND OF THE INVENTION

High intraocular pressure (IOP) is an important risk factor for different ocular pathologies. Pharmacological and non-pharmacological treatments (such as laser-based therapies and surgical processes) are used in medical routine to try to reduce IOP values in situations of ocular hypertension. However, today there are many investigations that seek new forms of therapy based on the prevention of ocular hypertension, or at least, prevent or delay the damage produced by high levels of IOP in the optic nerve, which can cause functional limitations of the eye and even blindness ( Peeters et al. Acta Ophthalmol.

2010, 88 ( 1):5-11).

There are many studies that suggest that a good diet and exercise can prevent increased IOP, although the mechanisms and dietary components behind this fact remain to be recognized. Some studies point to oxidative stress as one of the mechanisms involved in the increase in IOP, due to the oxidation of DNA at the level of the trabecular meshwork that could reduce the drainage of aqueous humor, thus increasing IOP. However, different studies carried out with antioxidant substances indicate that it is still early to postulate any antioxidant substance as a preventive/therapeutic against elevated IOP ( Pasquale et al. J Glaucoma, 2009, 18(6):423-428). Furthermore, the possible role of anti-inflammatory molecules in reducing IOP levels has been highlighted ( Doucette et al. Ophthalmic Genet, 2017, 38(2):108-116).

On the other hand, it seems that substances with cardioprotective properties, such as high intake of omega-3, could be associated with a reduction in IOP ( Downie et al. Transí vis Sci Technol, 2018, 1;7(3):1).

For all these reasons, more research is required in this regard, given that the results are contradictory, suggesting that there may be several mechanisms involved in lowering IOP, so different substances in certain isolated situations could not have hypotensive activity.

The wild olive tree (Olea europaea L. var. sylvestris or oleaster) constitutes a primitive variety of olive tree highly adapted to the climatic contrasts typical of the Mediterranean climate ( Mercado-Blanco et al, Physiological and Molecular Plant Pathoíogy, 2003, 63 , 91-105.). Smaller in size than the cultivated olive tree, its natural distribution covers the most thermal territories of the Mediterranean Sea basin and the southern Portuguese coast, also being found in the Canary Islands and Madeira. Currently, studies have been carried out to determine the chemical composition of olive oil (ACE) and analyze its antioxidant properties on the retina and choroid in a situation of high blood pressure (HTN); The benefit of olive oil in this context could be attributed to a peculiar chemical composition, where the proportion of various major components differs with respect to the reference extra virgin olive oil ( Santana-Garrido et al. Antioxidants, 2020, 18, 9 ( 9):885). On the other hand, the anti-inflammatory properties of ACE have also been demonstrated; that prevent alterations in retinal function produced under a context of HTN thanks to the diet enriched in ACE ( Santana-Garrido et al. Foods, 2021, 25;10 ( 9):1993).

It should be noted that today it is well established by the scientific community that blood pressure and intraocular pressure values are regulated independently and are different medical conditions and not related in their etiology and treatment {Barbosa-Breda et al. Acta Ophthalmol, 2019, 97(4):e487-e492; Skrzypecki et al. Curr Med Res Opin, 2018. 34(3):521-529). So much so that the pharmacological management of HTN and high IOP values are totally different, such that the drugs most used to reduce IOP (carbonic anhydrase inhibitors and prostaglandin analogues) as well as the new therapies that are being developed ( Mansouri et al. Surv Ophthalmol, 2020, 65(2):171-186), are totally different from those used for HTN.

This brings us to the current situation in which the study of therapeutic agents and the mechanisms of action involved in both pathologies are approached from a different point of view, indicating that an association between arterial hypertension and ocular hypertension does not always appear, and that it will depend on the context in which we speak.

DESCRIPTION OF THE INVENTION

The present invention relates to wild olive or wild olive oil ( Olea europea L. var. Sylvestris or oleaster) as an ocular hypotensive agent for the treatment and/or prevention of ocular hypertension and ocular diseases caused or favored by said hypertension, such as, for example , keratoconus, uveitis and high myopia.

The inventors have demonstrated a reduction in intraocular pressure (IOP) values in an animal model with high intraocular pressure using a diet enriched with olive oil, particularly with 12% w/w (Figure 1).

Thus, in a first aspect, the present invention relates to olive oil, hereinafter the “oil of the invention”, or a pharmaceutical composition comprising said olive oil, hereinafter the “pharmaceutical composition of the invention”. invention”, for use in the treatment and/or prevention of ocular hypertension and/or ocular diseases caused by said ocular hypertension in a subject, hereinafter the “use of the invention”.

The term “olive oil” as used in the present invention refers to the oil extracted from wild olive or wild olive ( Olea europea var. Sylvestris or oleaster). This oil has a higher proportion of triterpene compounds (340.3±8.6 mg/Kg), sterols (1735±18.99 mg/Kg) and tocopherols (343.8±7.3 mg/Kg) in the oil. of wild olive with respect to the standards normally observed in virgin olive oils (153.12±1.25 mg/Kg for triterpenes, 1531±15.86 mg/Kg for sterols and 221.76±1.79 mg/Kg for tocopherols). The methods for obtaining and extracting oils are widely known in the state of the art.

The term "treatment", as understood in the present invention, refers to combating the effects caused by ocular hypertension and/or ocular diseases caused or promoted by said hypertension such as, for example, keratoconus, uveitis and high myopia, in a subject (preferably mammal, and more preferably a human) including:

(i) inhibit the disease or pathological condition, that is, stop its development; (ii) alleviate the disease or pathological condition, that is, cause the regression of the disease or pathological condition or its symptomatology;

(iii) stabilize the disease or pathological condition.

The term "prevention" as understood in the present invention consists of preventing the occurrence of a disease, specifically ocular hypertension and/or ocular diseases caused or favored by said hypertension, that is, preventing the occurrence of the disease or pathological condition in a subject (preferably mammal, and more preferably a human), in particular, when said subject has a predisposition to suffer from the disease.

The term "ocular hypertension" as used in the present invention refers to the increase in the pressure inside the eye, that is, the intraocular pressure (IOP), above the range that is considered normal and is above 21 mmHg. IOP is the pressure exerted, mainly, by the aqueous humor found inside the eye. In a healthy eye, the aqueous humor is a flow that is continuously dynamic, with a balance existing between its formation by the ciliary processes and its drainage through Schlemm's canal. However, different alterations can unbalance this flow, making it impossible for this fluid to be renewed and producing an accumulation of aqueous humor that will produce an increase in IOP. Normal IOP values are between 10 and 21 millimeters of mercury (mmHg) in humans, while tonometry carried out in rodents shows a normal IOP range between 10-15 mmHg. High levels of IOP produce a situation of ocular hypertension that can trigger severe damage to different ocular structures such as the cornea or the optic nerve, and may even favor the generation of risk factors for different ocular pathologies such as keratoconus, uveitis and great myopia.

In a particular embodiment of the use of the invention, the ocular disease is selected from the list consisting of: keratoconus, uveitis and high myopia.

Additionally, the olive oil may be included in a composition pharmaceutical. Thus, another aspect of the present invention is a pharmaceutical composition comprising olive oil for use in the treatment and/or prevention of ocular hypertension and/or ocular diseases caused by said ocular hypertension.

The term "pharmaceutical composition" refers to a set, mixture, combination of components or substances that comprises olive oil in any concentration, and that improves the state of health of the subject, in particular it implies a preventive or therapeutic effect on hypertension. ocular. The pharmaceutical composition can be for human or veterinary use. The term “pharmaceutical composition for human use” refers to a substance or combination of substances with properties for the treatment or prevention of ocular hypertension in humans or that can be used in humans or administered to humans for the purpose of restoring, correct or modify physiological functions by exercising a pharmacological, immunological or metabolic action, or establishing a medical diagnosis. The term "pharmaceutical composition for veterinary use" refers to a substance or combination of substances with curative or preventive properties with respect to animal diseases or that can be administered to the animal in order to restore, correct or modify its physiological functions by exercising an action. pharmacological, immunological or metabolic, or establishing a veterinary diagnosis.

In another particular embodiment, the pharmaceutical composition further comprises at least one vehicle and/or a pharmacologically acceptable excipient.

The term "vehicle" or "carrier" refers to a substance, preferably an inert substance, that facilitates the incorporation of other compounds, that allows better dosage and administration or improves the consistency and form of the pharmaceutical composition for use in the treatment or prevention of ocular hypertension. Therefore, the vehicle is a substance that is used in the medicine to dilute any of the components of the pharmaceutical composition up to a certain volume or weight; or that, even without diluting said components, it is capable of allowing better dosage and administration or giving consistency and shape to the medication. When the presentation form is liquid, the pharmaceutically acceptable vehicle is the diluent.

The term "excipient" refers to a substance that helps the absorption of any of the components of the pharmaceutical composition, stabilizes said components, modify their organoleptic properties or determine the physical-chemical properties of the pharmaceutical composition and its bioavailability. Thus, the excipients could have the function of keeping the components together, such as starches, sugars or cellulose, the function of sweetening, the function of coloring, the function of protecting the medication, such as isolating it from air and/or humidity, the function of filling of a tablet, capsule, pill or any other form of presentation such as, for example, dibasic calcium phosphate, disintegrating function to facilitate the dissolution of the components and their absorption in the intestine, without excluding other types of excipients not mentioned in this paragraph.

Furthermore, as understood by those skilled in the art, the excipient and the vehicle must be pharmacologically acceptable. The term “pharmaceutically acceptable” refers to the fact that the vehicle or excipient must allow the activity of the compounds of the pharmaceutical composition, in particular olive oil, that is, it must be compatible with said components, so that it does not cause harm. to the organizations to which it is administered.

The pharmaceutical composition can be presented under any clinically permitted form of administration and in a therapeutically effective amount. For example, it may be in a form adapted for ophthalmic, oral, sublingual, nasal, intracatecal, bronchial, lymphatic, rectal, transdermal, intravenous, intraperitoneal, orogastric, intracolonic, inhaled or parenteral administration.

In another particular embodiment, the pharmaceutical composition of the invention for use in the treatment or prevention of ocular hypertension is administered ophthalmically, orally, orogastrically or intracolically.

The pharmaceutical composition of the invention for use in the treatment or prevention of ocular hypertension can be formulated in solid, semi-solid, liquid or gaseous forms, such as tablet, capsule, pill, powder, granule, ointment, solution, suppository, injection , inhalant, gel, microsphere or aerosol. The form adapted for oral administration is selected from the list comprising, but not limited to, drops, syrup, herbal tea, elixir, suspension, extemporaneous suspension, drinkable vial, tablet, capsule, granules, seal, pill, tablet, lozenge, troche or lyophilized.

The oil or pharmaceutical composition of the invention can be used in the treatment and prevention of ocular hypertension in any subject. As used herein, the term “subject” or “individual” refers to any animal. Examples of animals include, but are not limited to, fish, birds, amphibians, reptiles and mammals. Examples of mammals include, but are not limited to, horses, pigs, rabbits, sheep, goats, cows, dogs, cats, guinea pigs, rats, mice, non-human primates, and humans. The term does not indicate a particular age or sex.

In another particular embodiment, the subject of the invention is a mammal, preferably a primate, more preferably, a human being of any sex or age.

The oil or pharmaceutical composition of the invention can be administered to the subject in a therapeutically effective dose, which can vary over a wide range. In the present invention, the terms "therapeutically effective dose" or "therapeutically effective amount", used interchangeably herein, refer to that amount or dose of olive oil that when administered to a subject, preferably a mammal, and more preferably to a human, is sufficient to produce the prevention and/or treatment of ocular hypertension. The therapeutically effective amount will vary, for example, depending on the metabolic stability and duration of action of the olive oil; the subject's age, body weight, general health, sex, and diet; the mode and time of administration; excretion rate, combination with other drugs; the severity of the particular disease or pathological condition of said subject. It is routine practice for a person skilled in the art, for example, for a medical specialist, to determine the therapeutically effective dose for each subject, preferably in a human, according to his or her own knowledge and the physiological conditions or variables of the subject.

In another particular embodiment of the use of the invention, the olive oil is administered to the subject in a therapeutically effective dose, preferably daily, through a diet enriched with a percentage of between 10 and 15% w/w of said oil.

In another more particular embodiment of the use of the invention, the olive oil is administered through a diet enriched with a percentage of 12%, 13% or 14% w/w. of said oil, preferably with a percentage of 12% w/w.

In the present invention the term “diet” refers to a basic composition of nutrients that must be ingested daily. Particularly, the term “enriched diet” refers to the set of substances that are ingested regularly to which, in the case of the present invention, 12% w/w of olive oil is added to its total.

In another particular embodiment of the use of the invention, the olive oil is administered to the subject in a therapeutically effective dose, preferably daily, through a daily dose between 1.3 and 1.9 mL/Kg body weight.

In another more particular embodiment of the use of the invention, the olive oil is administered through a daily dose of 1.5 mL/Kg body weight.

In another particular embodiment of the use of the pharmaceutical composition of the invention, olive oil is the adjuvant in said pharmaceutical composition.

In another particular embodiment of the use of the pharmaceutical composition of the invention, where said composition also comprises other agents for the treatment of ocular hypertension.

As understood by an expert in the field, olive oil can be included in a nutritional or food composition, for use in the prevention of ocular hypertension.

Therefore, another aspect of the present invention is a food or nutritional composition, hereinafter the "nutritional composition of the invention", which comprises olive oil for use in the prevention of ocular hypertension and/or ocular diseases caused by due to said ocular hypertension.

The terms "olive oil", "prevention" and "ocular hypertension" have been described previously herein and apply equally to this aspect of the invention, as well as to all its particular embodiments (alone or in combination). .

The term "food composition" or “nutritional composition” herein The invention refers to a food composition or food that, independently of providing nutrients to the subject who takes it, beneficially affects one or several functions of the organism, so as to provide a better state of health and well-being. As a consequence, said nutritional composition may be intended for the prevention of ocular hypertension.

In another particular embodiment of the use of the nutritional composition of the invention, the ocular disease is selected from the list consisting of: keratoconus, uveitis and high myopia.

In another particular embodiment of the use of the nutritional composition of the invention, said nutritional composition comprises between 1.3 and 1.9 mL/Kg body weight/day of olive oil.

In another more particular embodiment of the use of the nutritional composition of the invention, said nutritional composition comprises 1.5 mL/Kg body weight/day of olive oil.

DESCRIPTION OF THE FIGURES

Figure 1. Weekly measurement of intraocular pressure in the different experimental groups. ap<0.05 vs CONTROL; bp<0.05 vs L-NAME; cp<0.05 vs OLIVE; dp<0.05 vs OLIVA; ep<0.05 vs LN+ACE.

EXAMPLES

Next, the invention will be illustrated through tests carried out by the inventors, which demonstrate the effectiveness of the product of the invention.

Male mice of the C57/J strain aged between 10-12 weeks were used, establishing six experimental groups of animals:

• Group A: normotensive mice on a non-enriched diet (CONTROL). • Group B: normotensive mice with a diet rich in 12% w/w olive oil (ACE).

• Group C: normotensive mice with a diet rich in 12% w/w olive oil extra virgin (OLIVE).

• Group D: mice with ocular hypertension produced by 45 mg of L-NAME/kg body weight/day with a non-enriched diet (L-NAME).

• Group E: mice with ocular hypertension produced by 45 mg of L-NAME/kg body weight/day with a diet rich in 12% w/w olive oil (LN+ACE). • Group F: mice with ocular hypertension produced by 45 mg of L-NAME/kg body weight/day with a diet rich in 12% w/w extra virgin olive oil (LN+OLIVA).

The diet group enriched with olive oil was compared with a group supplemented with extra virgin olive oil. Both the olive oil and the extra virgin olive oil are supplied by the “Molino de Monda” oil mill, which is located in the Sierra de las Nieves area of Malaga, and which produces both oils following the same production conditions. extraction and production. The treatment with the oils was carried out using a commercial feed enriched with 12% w/w of the oils: with olive oil (the ACE and LN+ACE groups), and with extra virgin olive oil (in the groups OLIVE and LN+OLIVE).

On the contrary, the rats in the Control group and L-NAME group were fed with the unenriched commercial feed. Both the L-NAME and oil treatments were maintained for 6 weeks. During this period, animals were maintained under standard conditions (23+/-1°C, 12-hour light/12-hour dark cycles). All mice were fed ad libitum with free access to their drink.

During the treatment time, intraocular pressure was measured weekly using rebound tonometry (Tonolab, loare) following a protocol well described in the literature ( Tribble et al. Redox Biol, 2021, 43, 101988). To carry out this protocol, the animals were accustomed to performing the tonometry the week before the beginning of the treatments. Intraocular pressure recordings were performed weekly in live, awake, unrestrained animals between 8:00 am and 11:00 am to avoid the effects of circadian rhythms on intraocular pressure (IOP). The measurement was taken at all times on the central cornea and the results obtained come from the arithmetic mean of at least 5 measurements per animal/eye.

The results show that a diet enriched in 12% w/w olive oil, administered to animals with ocular hypertension for 6 weeks, decreases intraocular pressure (Figure 1) and acts as an ocular protective element against ocular hypertension.

Furthermore, our results support a greater ocular hypotensive effect of olive oil compared to extra virgin olive oil, which was obtained and processed under the same conditions as the olive oil used.

Claims (10)

1. Olive oil, or pharmaceutical composition comprising it, for use in the treatment and/or prevention of ocular hypertension and/or ocular diseases caused by said ocular hypertension. 2. Oil for use according to claim 1 wherein the ocular disease is selected from the list consisting of: keratoconus, uveitis and high myopia. 3. Oil for use according to claim 1 or 2 wherein the olive oil is administered through a diet enriched with a percentage of between 10 and 15% w/w of said oil. 4. Oil for use according to claim 3 wherein the olive oil is administered through a diet enriched with a percentage of 12% w/w of said oil. 5. Oil for use according to claim 1 or 2 wherein the olive oil is administered through a daily dose between 1.3 and 1.9 mL/Kg body weight. 6. Oil for use according to claim 5 wherein the olive oil is administered through a daily dose of 1.5 mL/Kg body weight. 7. Oil for use according to any of claims 1 to 6 wherein the olive oil is the adjuvant in the pharmaceutical composition. 8. Oil for use according to any of claims 1 to 7, wherein the composition further comprises other agents for the treatment of ocular hypertension. 9. Nutritional composition comprising olive oil for use in the prevention of ocular hypertension and/or ocular diseases caused by said ocular hypertension. 10. Nutritional composition according to claim 9 wherein the ocular disease is selected from the list consisting of: keratoconus, uveitis and high myopia.