JP-2026076176-A - Folic acid preparations for the treatment of ophthalmic diseases

Abstract

[Problem] To provide a formulation for use in the treatment of systemic diseases and ophthalmic diseases associated with elevated retinal venous pressure. [Solution] A formulation containing at least one folic acid (folate) is provided. [Selection Diagram] None

Inventors

• ウルマン、マーティン
• ビースラー、ゲルド
• フラマー、ヨセフ

Assignees

• アプロフォル アクチエンゲゼルシャフト

Dates

Publication Date

20260511

Application Date

20251225

Priority Date

20200302

Claims (12)

1. A formulation containing at least one folic acid (folate) for use in the treatment of systemic and ophthalmic diseases associated with elevated retinal venous pressure.
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, for use in the treatment of an ophthalmic disease.
3. The formulation according to claim 2, for use in the treatment of an ophthalmic disease characterized by glaucoma being primary open-angle glaucoma, primary closed-angle glaucoma, or normal-tension glaucoma.
4. A formulation according to any one of claims 1 to 3, further comprising a sulfur donor compound, preferably N-acetylcysteine.
5. The formulation according to any one of claims 1 to 4, further comprising at least one vitamin of the B complex, preferably selected from the group consisting of vitamin B1 , vitamin B2 , vitamin B6 , and vitamin B12 .
6. A formulation according to any one of claims 1 to 5, further comprising arginine or an arginine ester.
7. A formulation according to any one of claims 1 to 6, further comprising a choline donor, preferably betaine.
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, preferably vitamin D3 .
11. The formulation according to any one of claims 1 to 10, characterized in that the folate cation 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 folate anion 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.

Description

This invention relates to folic acid (folate) compositions and the technology for the management or treatment of ophthalmic diseases associated with elevated retinal venous pressure. 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. Retinopathy encompasses a variety of conditions. Examples include diabetic retinopathy (DR), hypertensive retinopathy, and hereditary retinopathy. Diabetic retinopathy, also known as diabetic ophthalmopathy, is a disease in which diabetes causes damage to the retina. It is a leading cause of blindness in developed countries. Diabetic retinopathy (DIR) 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 DRIRS. 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, sometimes improving and sometimes worsening. 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. 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 diabetic patients will experience vision loss associated with macular edema. Optical coherence tomography (OCT) can reveal areas of retinal thickening due to fluid accumulation. As the second stage of diabetic retinopathy (DR), the formation of abnormal neovascularization (neovascularization associated with elevated vascular endothelial growth factor (VEGF) levels) at the back of the eye is called proliferative diabetic retinopathy (PDR). Because these new blood vessels are fragile, they 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, and these spots usually disappear after a few hours. 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. The formation of drusens 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. Wang J. et al., Eye and Vision, 2019, 6:21, reported a series of cases of patients with non-proliferative diabetic retinopathy or hypertensive retinopathy 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. 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 li