Folic acid preparations for the treatment of ophthalmic diseases

Abstract

Compositions containing at least one folic acid (folate) useful for treating ophthalmic disorders associated with elevated retinal venous pressure are described.

Description

[Technical Field]

[0001] The present invention relates to folic acid (folate) compositions and the technology for the management or treatment of ophthalmic diseases associated with elevated retinal venous pressure. [Background technology]

[0002] Diseases and degenerative disorders of the optic nerve and retina are the leading causes of visual impairment and blindness worldwide. Approximately 300 million people globally suffer from various forms of visual impairment due to eye diseases. While a high percentage—around 80%—of visual impairments are preventable, there are still unmet needs.

[0003] There are various types of retinopathy. Examples of retinopathy include diabetic retinopathy (DR), hypertensive retinopathy, and hereditary retinopathy.

[0004] Diabetic retinopathy, also known as diabetic ophthalmopathy, is a disease in which diabetes causes damage to the retina. In developed countries, it is a leading cause of blindness.

[0005] Diabetic retinopathy affects many patients who have had diabetes for more than 20 years. Effective treatment and eye monitoring can prevent the majority of new cases. The longer the duration of diabetes, the higher the probability of developing diabetic retinopathy.

[0006] Diabetic retinopathy often has no early warning symptoms. However, people with macular edema are generally more likely to experience blurred vision, making activities such as reading and driving difficult. In some cases, vision may fluctuate throughout the day.

[0007] The first stage of diabetic retinopathy (DR), also known as non-proliferative diabetic retinopathy (NPDR), is usually asymptomatic. The only way to detect NPDR is through fundus examination, which can reveal microaneurysms (tiny bulges in the arterial wall filled with blood, or capillary sacs) and exudate. Fluorescein angiography is particularly effective in showing retinal vascular stenosis or occlusion (insufficient blood flow, retinal ischemia), i.e., areas of tissue non-perfusion. It can also observe intraretinal hemorrhage, lipid exudation, retinal edema, retinal microinfarcts, IrMA (intraretinal microvascular anomalies), venous beading, and elevated retinal venous pressure.

[0008] Macular edema is a condition in which the contents of blood vessels leak into the macula. It can occur at any stage of diabetic retinopathy (DR), but is more common in proliferative DR. Symptoms include blurred vision and uneven darkness or distortion in the eyes. Ten percent of people with diabetes will experience vision loss associated with macular edema. Optical coherence tomography (OCT) can reveal areas of the retina that have thickened due to fluid accumulation.

[0009] As the second stage of diabetic retinopathy (DR), abnormal neovascularization (neovascularization associated with elevated vascular endothelial growth factor (VEGF) levels) occurs at the back of the eye, a condition called proliferative diabetic retinopathy (PDR). These neovascularizations are fragile and can leak, rupture, and bleed (vitreous hemorrhage), causing blurred vision. The first time this bleeding occurs, it may not be very severe. In most cases, only a few blood clots or spots remain in the field of vision, but these spots usually disappear after a few hours.

[0010] Macular degeneration (MD) is one of the most common retinal diseases. MD refers to the loss of photoreceptors in the macula, the central part of the retina that contributes to high visual acuity. Age-related macular degeneration (AMD) has two types: "dry" and "wet." Approximately 10% of AMD patients have wet, exudative neovascular AMD, characterized by abnormal blood vessel growth through the retinal pigment epithelium (RPE), leading to hemorrhage, exudation, scarring, and serous retinal detachment. Drusen formation is a typical example of dry AMD. 90% of AMD patients have the dry type, characterized by atrophy of the retinal pigment epithelium and loss of photoreceptors in the macula. While photodynamic therapy and VEGF inhibitors used to treat wet AMD can sometimes alleviate symptoms, there is currently no effective treatment for any type of AMD.

[0011] Wang J. et al., Eye and Vision, 2019, 6:21, reported a series of cases in which patients with non-proliferative diabetic retinopathy or hypertensive retinopathy were treated with an unprescription multivitamin composition. All patients had one or more MTHFR polymorphisms. The main findings were a reduction in retinal hemorrhage and microaneurysms, and a reduction in exudate and macular edema. However, no significant changes in retinal blood flow were observed.

[0012] Richardson et al. (US6207190) disclose a composition comprising a mixture of four functional groups of biofactors for the treatment of chronic glaucoma. These four functional groups are a cGMP enhancer containing folic acid, an intracellular calcium signaling modulator containing magnesium, a cell membrane integrity maintainer containing α-tocopherol, and a hyperinsulinemia regulator containing α-lipoic acid. The composition is primarily intended to improve local and systemic endothelial health. Folic acid is listed as a component of the composition, but methyl-tetrahydrofolate and formyl-tetrahydrofolate are not. Intraocular pressure (IOP) is described as an important factor in chronic glaucoma.

[0013] Brian Buell (WO2011 / 163301) described using downstream folate (folate) compounds to optionally methyl B in patients with any metabolic disorder related to folate metabolism or intertwined metabolic cycles. 12 This paper describes methods for treating visual impairment in non-folate-deficient subjects, in combination with one or more of vitamin B6 and vitamin D3. Visual impairment includes neuropathy, retinopathy, macular degeneration, and associated ocular lesions. In particular, malfunctions in the folate (folate) cycle and BH4 cycle are addressed when the malfunction is caused by one or more of the C677T and A1298C mutations. L-methylfolate is a preferred downstream folate (folate) compound. The role of intraocular pressure, particularly the role of retinal venous pressure in ocular diseases, and compositions for use in their treatment are not described.

[0014] Sosnowski et al. (US2004 / 0087479) linked (elevated) homocysteine ​​levels to glaucoma, tardive dyskinesia, and cardiovascular disease, and suggested that folic acid or folate, vitamin B6, and vitamin B6 were associated with these conditions. 12 This document discloses diseases that can be treated with compositions containing dextromethorphan (DM) in combination with other substances. While generally referred to as folate, it may be in the form of folic acid, mono- and polyglutamyl folate, dihydro- and tetrahydro-folate, methyl- and formyl-folate. Folic acid as folate is highly preferred. The composition may also contain numerous further compounds, such as vitamin E, lecithin, and β-carotene. Dextromethorphan and other NMDA receptor antagonists are known to treat glaucoma. This composition may be used to lower blood homocysteine ​​levels without the side effects of a single component used at high concentrations. There is no disclosure regarding intraocular pressure and retinal venous pressure.

[0015] EP3616700 (Aprofor) describes a composition containing multiple folate salts for use in the treatment of eye diseases associated with the presence of elevated intraocular pressure (IOP). Furthermore, elevated IOP due to insufficient ocular drainage is described as the most frequent cause of glaucoma, a condition resulting from several different eye diseases that cause vision loss due to damage to the optic nerve. Drug therapies proven effective for glaucoma lower IOP by reducing aqueous humor production or promoting drainage of the eye. Retinal venous pressure (RVP) is not mentioned.

[0016] Cybulska-Heinrich et al., in The EMPA Journal, 2015, 6:5, described the association between diabetic retinopathy (DR) and (high) retinal venous pressure. Their results showed that RVP was significantly elevated in diabetic patients who developed DR. RVP was not elevated in diabetic patients without DR. This indicates that RVP is clearly higher than IOP in DR patients.

[0017] Glaucoma is a disease resulting from several different systemic and ocular conditions that cause vision loss due to damage to the optic nerve. The most common cause of glaucoma is impaired drainage of the eye, leading to elevated intraocular pressure (IOP). Glaucoma often develops with age, but can also occur as a result of eye injury, inflammation, tumors, or the progression of cataracts or diabetes. It can also be caused by elevated IOP due to steroid treatment. Drug therapies considered effective for glaucoma lower IOP by reducing aqueous humor production or promoting drainage of the eye.

[0018] There are various causes of elevated IOP, one of which is pseudoexfoliation syndrome. Pseudoexfoliation syndrome, often abbreviated as PEX, and sometimes as PES or PXS, is an age-related systemic disease that primarily affects the eye and is characterized by the accumulation of tiny, granular amyloid-like protein fibers. Exfoliation syndrome (XFS) is an age-related disease in which abnormal fibrous extracellular material is produced and accumulates in many eye tissues. Its ocular symptoms extend to all structures of the anterior segment of the eye, as well as the conjunctiva and orbital structures.

[0019] Normal-tension glaucoma (NTG), also known as hypotension or normal-tension glaucoma, is a type of glaucoma in which damage to the optic nerve occurs without intraocular pressure exceeding the normal range. Generally, the "normal" intraocular pressure range is 12-22 mmHg. The most prominent cause of NTG is disturbance of ocular blood flow. A frequently occurring sign is elevated RVP (Fang et al, BMC Ophthalmology, 2014 14, 121).

[0020] Flumer syndrome (FS) is a phenotype in individuals predisposed to altered vascular responses to stimuli such as cold, psychological stress, and high altitude. Main symptoms include cold hands and / or feet, low blood pressure, prolonged sleep onset, decreased thirst, increased sensitivity to smells, pain, vibrations, and certain medications. Individuals with FS are often ambitious and successful, but can also be perfectionistic and sometimes gloomy. Common signs include altered gene expression, prolonged cessation of blood flow in nail fold capillary angiography after cold stimulation, impaired autoregulation of ocular blood flow, and decreased retinal vasodilation after flashing light stimulation. Retinal venous pressure is, on average, higher, and retinal astrocytes are more frequently activated. FS is more common in women than men, leaner than obese individuals, younger than older individuals, college graduates than blue-collar workers, and those working indoors rather than outdoors. Related conditions include normal-tension glaucoma, occlusion of ocular blood vessels, retinitis pigmentosa, multiple sclerosis, tinnitus, and sudden hearing loss.

[0021] Small vessel disease (also known as microangiopathy or microvascular disease) is a vascular disorder that affects the small vessels in the body, i.e., a disease of the blood vessels. Coronary microvascular disease is a type of coronary heart disease (CHD) that affects the arterioles and capillaries of the heart. Cerebral small vessel disease refers to a group of diseases that affect the small arteries, arterioles, veins, and capillaries of the brain. Small vessel diseases caused by aging and hypertension and cerebral amyloid angiopathy are the most common diseases. Cerebral small vessel disease (SVD) is a term that encompasses various abnormalities related to the small vessels of the brain. Small vessel disease is known to be a contributing factor to vascular cognitive impairment and vascular dementia. In Smallwood et al., Neuropathology and Applied Neurobiology, 2012, 38, 337-343, cerebral small vessel disease is described as the second most significant cause of cognitive impairment in the elderly, after Alzheimer's disease. This study showed a significant correlation between the severity of the pathological condition of SVD and cognitive impairment using an image-based scoring system.

[0022] In Fang et al., BMC Ophthalmology, 2014 14, 121, the effect of FS on retinal venous pressure was investigated. The aim of the study was to measure the retinal venous pressure (RVP) of the eyes of primary open-angle glaucoma (POAG) patients and healthy subjects, regardless of the presence or absence of FS. As a result, it was shown that RVP was higher in subjects with FS, especially in subjects with FS who had glaucoma.

[0023] Currently available treatments are effective in delaying the progression of ophthalmic diseases. However, in most cases, they cannot cure eye diseases. There is a continuing need for effective treatments for ophthalmic diseases or eye diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal and choroidal ischemia, glaucoma, cataract, retinitis pigmentosa, choroidal neovascularization, retinal degeneration, and ocular surface diseases.

[0024] In addition to ophthalmic reasons, an increase in RVP may be caused by an increase in intracranial pressure or orbital veins.

[0025] Retinal venous pressure (RVP) can be defined as the pressure of the pulsating veins in the retina. This includes the central retinal venous pressure (also called central retinal vein pulsation pressure (CRVPP)) when the central retinal vein pulsates, and the branch retinal venous pressure when the branch retinal veins (also called semi-veins and quadrant veins) pulsate.

[0026] In Pillunat KR, et al., Br J Ophthalmol 2014, 98, 1374-1378, the role of central retinal vein pulsation pressure (CRVPP) was evaluated in patients with open-angle glaucoma with controlled intraocular pressure (IOP) at the initial, moderate, and advanced stages of the disease, and compared with a healthy control group. In more advanced cases of glaucoma, CRVPP appeared to be much higher than previously thought.

[0027] The cause of the eye that leads to an increase in RVP is thought to be either mechanical compression or functional stenosis of the veins at the exit of the eye. As a result, the perfusion pressure decreases, which increases the risk of hypoxia. An increase in RVP also increases the trans-wall pressure, thereby increasing the risk of retinal edema.

[0028] In Gugleta K, Klinisches Monatsblatt Augenheilkunde, 2018, 235, 140-145, the significance of endothelin-1 in glaucoma is described. Endothelin-1 is a ubiquitous molecule present in virtually all tissues. Its main physiological function is the regulation of blood vessel diameter and thus the regulation of blood supply to tissues. It is secreted locally and acts mainly locally. Endothelin-1 is involved in the regulation of blood flow in the retina and optic nerve.

[0029] Flammer et al., The EMPA Journal, DOI 10.1186 / s13167-xxx-xxxx-1 describes the role of endothelin in retinal venous pressure (RVP). In healthy individuals, RVP is usually the same as or slightly higher than the intraocular pressure (IOP), but in patients with eye or systemic diseases, it often rises significantly. It should be noted that there is an error in the DOI in the original text you provided. I have left it as it is in the translation for you to check and correct if necessary. The correct DOI should be a valid link. Also, the "xxx" in the translation of ID=17 should be replaced with the correct numbers according to the actual DOI.[Overview of the Initiative]

[0030] The object of the present invention is to provide a formulation for use in the treatment of diseases, particularly ophthalmic diseases associated with elevated retinal venous pressure. [Modes for carrying out the invention]

[0031] Retinal venous pressure (RVP) is considered normal when it is equal to or a few mmHg higher than intraocular pressure (IOP). To measure RVP, an intraocular pressure (IOP) is increased until the target vein pulsates, using a fundus sphygmometer (such as a low contact lens dynamometer) or an IOPstim system (manufactured by Imedos). This applied force is also called ophthalmodynamometric force (ODF). In other words, if spontaneous venous pulsation is present (ODF=0), RVP is equal to IOP. If spontaneous venous pulsation is absent, the ODF required to induce spontaneous venous pulsation is measured, and RVP is calculated as RVP = ODF + IOP.

[0032] Retinal venous pressure may be measured using a fundus sphygmomanometer, for example, as described in Mozaffarieh M. et al., Graefes Arch Clin Exp Ophthalmol, 2014, 252, 1569–1571. Fundus hemostatic pressure may be measured as described in Mustur D. et al., The EPMA Journal, 2017, 8, 339–344.

[0033] Of course, elevated retinal venous pressure can occur even in clinically healthy eyes. However, despite this, it can still be a strong sign of systemic disease (such as autoimmune diseases).

[0034] The formulation according to the present invention for use in the treatment of eye diseases comprises at least one folate or a salt thereof. Eye diseases are associated with elevated retinal venous pressure.

[0035] Eye diseases associated with, related to, or caused by elevated retinal venous pressure include diabetic retinopathy, macular degeneration (MD), primary open-angle glaucoma (POAG), primary closed-angle glaucoma (PACG), and normal-tension glaucoma (NTG).

[0036] Folate is a reduced form of folic acid and can also be used in the formulation according to the present invention.

[0037] Folic acid is the oxidized form and the parent compound of biological folate. Due to its stability, folic acid is used in supplements and food fortification. However, folic acid is not metabolically active and requires reduction and one carbon substitution before being converted to 5-methyltetrahydrofolate in several enzymatically catalyzed steps. While the enzymatic conversion of folic acid itself may be incomplete, disrupted, or reduced at some points in its pathway, the effects of its deficiency can be amplified because folic acid metabolism is linked to other metabolic cycles; that is, dysfunction in one cycle can induce dysfunction in other metabolic cycles. A further form exists, 5-formyltetrahydrofolate, in which a formyl group is present instead of a methyl group.

[0038] In further embodiments, the formulation further comprises a sulfur donor compound, preferably N-acetylcysteine.

[0039] In another embodiment, the formulation further comprises at least one compound of the vitamin B complex. These B vitamins are preferably vitamin B1, vitamin B2, vitamin B6, and vitamin B 12 Selected from the group consisting of: Vitamin B 12 That is particularly preferable.

[0040] In yet another embodiment, the formulation further comprises arginine or an arginine ester.

[0041] Furthermore, the formulation may contain a choline donor. A preferred choline donor is betaine.

[0042] Furthermore, this composition may also contain the compound acetylcholine.

[0043] Furthermore, the preparation may also contain glucosamine.

[0044] In further embodiments, the composition comprises vitamin D, with vitamin D3 being particularly preferred.

[0045] In preferred embodiments, the folate salt consists of a folate and a cation as a counterion, the cation being selected from the group consisting of arginine, choline, acetylcholine, 1,1-dimethylbiguanidine, phenylethylbiguanidine, glucosamine, and dimethylaminoethanol.

[0046] The following folates are preferred: 5-formyl-(6S)-tetrahydrofolate, 5-formyl-(6RS)-tetrahydrofolate, 10-formyl-(6R)-tetrahydrofolate, 5-methyl-(6S)-tetrahydrofolate, 5-methyl-(6RS)-tetrahydrofolate, (6S)-tetrahydrofolate, 5,10-methylene-(6R)-tetrahydrofolate, 5,10-methenyl-(6R)-tetrahydrofolate, 5,10-diformyl-(6S)-tetrahydrofolate, and 5-methyl-10-formyl-(6S)-tetrahydrofolate. In other words, the anion of the folate salt is selected from the group consisting of the above folates.

[0047] The formulation can be manufactured in various forms, such as liquids, creams, and capsules.

[0048] The liquid form of the formulation is, for example, as follows, and the composition according to the present invention comprises a calcium salt, magnesium salt, sodium or zinc salt of levoleucovorin and one or more of the following: sodium gluconate, potassium gluconate, sodium lactate, potassium lactate, disodium glycerophosphate salt or dipotassium glycerophosphate salt. A cation such as arginine may also be used as the salt of levoleucovorin.

[0049] The composition may or may not contain additional excipients. Preferably, the composition does not contain benzyl alcohol, tromethamine, or monothioglycerol. Excipients such as mannitol for acceptable cake formation during the freeze-drying process, or sodium chloride and dextrose for adjusting osmotic pressure, may be added to the composition. The pH of the solution is typically in the range of 6.5 to 8.5 and can be adjusted during the manufacture of the pharmaceutical product, for example, using small amounts of hydrochloric acid or sodium hydroxide. The solution may contain antioxidants to prevent oxidative degradation.

[0050] The composition may contain at least one additional compound such as a calcium salt, sodium salt, magnesium salt, or zinc salt of leucovorin, (6R,S)-tetrahydrofolate, (6S)-tetrahydrofolate, 5,10-methylene-(6R,S)-tetrahydrofolate, 5,10-methylene-(6R)-tetrahydrofolate, 5-methyl-(6R,S)-tetrahydrofolate, or 5-methyl-(6S)-tetrahydrofolate, or a mixture of two, three, or more of these compounds.

[0051] A preferred composition according to the present invention comprises one or more of sodium gluconate, potassium gluconate, sodium lactate, potassium lactate, dipotassium glycerophosphate, or disodium glycerophosphate.

[0052] The following ratios are preferred for the amount of compounds in the composition. The composition preferably contains 0.8 to 6.0 moles, preferably 1.0 to 4.0 moles, of sodium gluconate, potassium gluconate, sodium lactate, or potassium lactate per mole of calcium salt, sodium salt, magnesium salt, or zinc salt of levoroicovorin. In actual embodiments, the composition preferably contains 1.5 to 3.0 moles of sodium gluconate or potassium gluconate per mole of calcium salt, magnesium salt, or zinc salt of levoroicovorin. Such a composition may contain a minimum of 0.8 moles, preferably 1.0 mole, preferably 1.5 moles, and a maximum of 6.0 moles, preferably 4.0 mole, preferably 3.0 moles, of sodium gluconate, potassium gluconate, sodium lactate, or potassium lactate per mole of salt.

[0053] Other compositions preferably contain 0.4 to 4.0 moles, preferably 0.5 to 3.0 moles, and more preferably 0.7 to 2.0 moles, of disodium glycerophosphate or dipotassium glycerophosphate per mole of calcium, sodium, magnesium, or zinc salt of levoleucovorin. Such compositions may contain a minimum of 0.4 moles, preferably 0.5 moles, and more preferably 0.7 moles, and a maximum of 4.0 moles, preferably 3.0 moles, and more preferably 2.0 moles, of disodium glycerophosphate or dipotassium glycerophosphate per mole of salt.

[0054] Other exemplary compositions or formulations suitable for inclusion in capsules are as follows, for example, formulations containing calcium salts of folate such as L-5-methyl-tetrahydrofolate or L-5-formyl-tetrahydrofolate, sulfur donor compounds such as N-acetylcysteine ​​or its salts, selenium-containing compounds such as L-selenomethionine, cholecalciferol, calcium D-pantothenate, vitamin B such as methylcobalamin. 12It contains components such as vitamin B6 (e.g., pyridoxal-5'-phosphate), vitamin B2 (e.g., riboflavin), vitamin B1 (e.g., thiamine mononitrate), zeaxanthin, lutein, vitamin E (i.e., D-α-tocopherol), vitamin C (e.g., calcium ascorbate), gluconates (e.g., copper gluconate), and zinc compounds (e.g., zinc oxide or zinc acetate).

[0055] For example, the formulation contains 0.2 mg to 2.7 mg of L-5-methyltetrahydrofolate calcium salt, 40 mg to 540 mg of N-acetylcysteine ​​or its salt, 0.005 mg to 0.06 mg of L-selenomethionine, 0.009 mg to 0.1 mg of cholecalciferol, 1 mg to 15 mg of D-pantothenate calcium, 0.003 mg to 0.1.5 mg of methylcobalamin, and 1 mg to 9 It contains the following ingredients: pyridoxal-5'-phosphate in mg, riboflavin in 2 mg to 30 mg, thiamine mononitrate in 0.2 mg to 4.5 mg, zeaxanthin in 1 mg to 3 mg, lutein in 4 mg to 15 mg, D-α-tocopherol in 1 mg to 16 mg, calcium ascorbate in 20 mg to 100 mg, copper gluconate in 0.1 mg to 2 mg, and zinc oxide in 7 mg to 80 mg.

[0056] The component N-acetylcysteine ​​can be used in the form of a free acid or one of its salts, for example, as a sodium salt or a calcium salt. N-acetylcysteine ​​can also exist in the form of N-acetylcysteine ​​amide. A further sulfur-donating compound is lipoic acid.

[0057] This composition more preferably contains one or more auxiliary substances selected from the group consisting of refined soybean oil, type NGM, partially hydrogenated soybean oil at 31° to 37°C, partially hydrogenated soybean oil at 36°C to 42°C, refined rapeseed oil, glyceryl monostellate, sunflower or soybean lecithin, and beeswax. The rapeseed oil or soybean oil provides protection of the active ingredients against light and moisture.

[0058] In another preferred embodiment, the composition comprises refined soybean oil, type NGM, soybean oil partially hydrogenated at 31°-37°C, soybean oil partially hydrogenated at 36°C-42°C, refined rapeseed oil, glyceryl monostearate, sunflower or soybean lecithin, beeswax, triglycerides with medium or longer chain lengths (medium chain length: C6-C 12 , long chain length: C 13 -C 24 ), phospholipids having at least one organic phosphate ester, and one or more auxiliary substances selected from the group consisting of ester compounds from alcohols with chain lengths C 20 -C 40 and medium or long chain fatty acids.

[0059] In another embodiment, the composition is contained in capsules such as, for example, soft gelatin capsules, vegan soft shell capsules or hard gelatin capsules. Soft gelatin capsules preferably contain gelatin, 98% glycerol, 86% glycerol, 70% sorbitol, titanium dioxide, sodium copper chlorophyllin and water.

[0060] An exemplary formulation for a cream contains a completely mixed phase. Phase A contains oil. Phase B contains glycerol and an emulsifier. Phase C contains an aqueous folate composition containing a physiologically effective amount of folate salt and optionally at least one compound selected from the group consisting of sodium gluconate, potassium gluconate, disodium glycerophosphate salt and dipotassium glycerophosphate salt. This may optionally contain further compounds such as pharmaceutically acceptable buffers, for example tris(hydroxymethyl)-aminomethane (TRIS), and pharmaceutically acceptable antioxidants, for example glutathione. Optional Phase D contains one or more opacifiers. Titanium dioxide can be used as a white dye. Alternatively, silicon dioxide can be used.

[0061] The folate preparation according to the present invention preferably contains, in the C phase, 0.1 mg to 1000 mg of at least one folate salt selected from the group consisting of calcium, magnesium, sodium, zinc, arginine, choline, acetylcholine, 1,1-dimethylbiguanidine, phenylethylbiguanidine, and dimethylaminoethanol salt of folate per 1 ml of polar solvent. Examples of polar solvents include water, methanol, ethanol, n-propanol, isopropanol, glycerin, and dimethyl sulfoxide. A mixture of such polar solvents may also be used. Arginine, choline, acetylcholine, 1,1-dimethylbiguanidine, phenylethylbiguanidine, glucosamine, and dimethylaminoethanol salt of folate are preferred.

[0062] In another embodiment, phase C contains 0.8 to 10 moles of sodium gluconate or potassium gluconate per mole of folate salt. If phase C contains disodium glycerophosphate or dipotassium glycerophosphate, these salts are preferably present at a concentration of 0.4 to 5 moles.

[0063] Preferably, the formulation according to the present invention contains an oil consisting of medium-chain triglycerols in phase A. The fatty acids of such medium-chain triglycerols are C6-C6. 12 It has a chain length in the range of [range]. Most preferably, it is caprylic / capric triglyceride oil. Furthermore, it may optionally contain dicarboxylic acid alcohols. Dicarboxylic acids are C2-C 10 The chain length is within the range of [specified range], and the alcohol is selected from the group consisting of methyl, ethyl, isopropyl, propyl, butyl, and pentyl alcohols.

[0064] The emulsifier used in the B phase of the formulation preferably has an HLB value of 5 or higher. The hydrophilic-lipophilic balance of a surfactant is an indicator of the degree of hydrophilicity or lipophilicity, and is determined by calculating values ​​for different regions of the molecule, as described by Griffin in 1954. The method for nonionic surfactants described by Griffin in 1954 works as follows: HLB = 20 x Mh / M, where Mh is the molecular weight of the hydrophilic portion of the compound and M is the total molecular weight of the compound. An HLB value of 0 corresponds to a completely lipophilic / hydrophobic molecule, and a value of 20 corresponds to a completely hydrophilic / oleophobic molecule. Emulsifiers with HLB values ​​in the range of 8 to 16 are suitable for stabilizing oil-in-water (o / w) emulsions.

[0065] Preferred emulsifiers are those with fatty acids C 14 ~C 20 It is a sucrose ester having a chain length within the range of [specified range]. Such a sucrose ester must have an HLB value of 5 or greater. Most preferred is a sucrose stearate that acts as an emulator. [Examples]

[0066] Example 1 In a preliminary study, patients were administered Ocufolin forte® (a folic acid preparation in capsule form), as described above. Treatment was administered for 10 days. No adverse effects were reported. Patient retinal venous pressure (RVP) was measured in both eyes as instructed before and after the treatment cycle. Before treatment, RVP was measured at 56 mmHg (right eye) and 59 mmHg (left eye). Intraocular pressure (IOP) was measured at 18 mmHg (both eyes). After treatment, RVP was measured at 32 mmHg (right eye) and 16 mmHg (left eye). IOP was measured at 16 mmHg (both eyes). These results indicate a significant decrease in RVP.

[0067] Hcy was measured from the patient's serum according to known methods. IOP was measured using a CorvisST® instrument. ODF was measured using a fundus sphygmomanometer according to Low. Retinal venous pressure (mmHg) was calculated according to the formula RVP = IOP + ODF.

[0068] Furthermore, when measurements were taken in patients with glaucoma, the following results were obtained. [Table 1] Table 1 The patient was supplemented with Ocufolin Forte® (1 capsule per day).

[0069] Example 2 As a continuation of the pilot study, the effects of vitamin supplementation containing L-methylfolate on retinal venous pressure and homocysteine ​​plasma levels in glaucoma patients were further evaluated.

[0070] The study included all patients with glaucoma and / or ocular vascular disease, including normal-tension glaucoma, primary angle-closure glaucoma, and primary open-angle glaucoma. The initial fundus blood pressure was 15 mmHg in either the optic nerve head (ONH) or a vein within the ONH. The patients' serum homocysteine ​​(HCy) concentration was higher than 12 μm / L.

[0071] Data were collected at a total of six time points. Baseline measurements of serum levels of IOP, RVP, and Hcy were performed at the first visit (time point: Pre-1). Baseline measurements were repeated at the second visit, after which vitamin supplementation was initiated (time point: Pre-2). Ocufolin® forte was used as a supplement at a dose of one capsule per day for three months. No side effects were reported with Ocufolin® forte supplementation.

[0072] During the treatment period, IOP and RVP were measured at 6 weeks and 3 months. For some patients, measurements were performed more frequently, such as at 2 weeks and 4 weeks (time points: Post 1, Post 2, Post 3, Post 4). Hcy was measured from the patient's serum according to known methods. IOP was measured using a CorvisST® instrument. ODF was measured using a fundus sphygmomanometer according to Low. Retinal venous pressure (mmHg) was calculated according to the formula RVP = IOP + ODF. [Table 2] N = Total number of veins measured Table 2 [Brief explanation of the drawing]

[0073] [Figure 1] Figure 1 shows the changes in RVP (Resource Value) before and during replenishment of Ocufolin®forte.

[0074] In addition, RVP levels decreased significantly in all patients, and mean homocysteine ​​(Hcy) serum levels also decreased statistically significantly after Ocufolin® forte supplementation compared to before supplementation.

Claims

1. A formulation comprising at least one folate or a salt thereof for use in reducing elevated retinal venous pressure in patients with systemic diseases and ophthalmic diseases.

2. The formulation according to claim 1, characterized in that the ophthalmic disease is selected from the group consisting of diabetic retinopathy, macular degeneration, and glaucoma.

3. The formulation according to claim 2, characterized in that the glaucoma is primary open-angle glaucoma, primary closed-angle glaucoma, or normal-tension glaucoma.

4. The formulation according to any one of claims 1 to 3, further comprising a sulfur donor compound.

5. The formulation according to any one of claims 1 to 4, further comprising at least one vitamin of the B complex.

6. The formulation according to any one of claims 1 to 5, further comprising arginine or an arginine ester.

7. The formulation according to any one of claims 1 to 6, further comprising a choline donor.

8. A formulation according to any one of claims 1 to 7, further comprising acetylcholine.

9. A formulation according to any one of claims 1 to 8, further characterized by containing glucosamine.

10. A formulation according to any one of claims 1 to 9, further characterized by containing vitamin D.

11. The formulation according to any one of claims 1 to 10, characterized in that the cation of the salt of forlate is selected from the group consisting of arginine, choline, acetylcholine, 1,1-dimethylbiguanidine, phenylethylbiguanidine, glucosamine, and dimethylaminoethanol.

12. The formulation according to one of claims 1 to 11, characterized in that the anion of the salt of folate is selected from the group consisting of 5-formyl-(6S)-tetrahydrofolate, 5-formyl-(6RS)-tetrahydrofolate, 10-formyl-(6R)-tetrahydrofolate, 5-methyl-(6S)-tetrahydrofolate, 5-methyl-(6RS)-tetrahydrofolate, (6S)-tetrahydrofolate, 5,10-methylene-(6R)-tetrahydrofolate, 5,10-methenyl-(6R)-tetrahydrofolate, 5,10-diformyl-(6S)-tetrahydrofolate, and 5-methyl-10-formyl-(6S)-tetrahydrofolate.

13. A formulation according to any one of claims 1 to 12, further comprising N-acetylcysteine.

14. A formulation according to any one of claims 1 to 13, further comprising betaine.

15. Vitamin D ３ A formulation according to any one of claims 1 to 14, further comprising:

16. Vitamin B １ Vitamin B ２ Vitamin B ６ , and vitamin B １２ The formulation according to any one of claims 1 to 15, further comprising at least one vitamin selected from the group consisting of the following.

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