FOLATE PREPARATIONS

Abstract

Preparations of folate for use in the treatment of eye disorders in the presence of elevated intraocular pressure. Methods of reducing intraocular pressure in a patient having an eye disease.

Claims

1. A preparation for use in reducing intraocular pressure in a patient having an eye disease, the preparation comprising at least one folate in reduced form.

2. (canceled)

3. The preparation according to claim 1, wherein the preparation comprises a salt of the at least one folate in reduced form and at least one sulfur compound or a salt thereof.

4. The preparation according to claim 1, wherein the preparation comprises a salt of the at least one folate in reduced form and at least one antioxidant or a salt thereof or at least one vitamin.

5. The preparation according to claim 1, wherein the preparation is a liquid or semi liquid formulation configured for a topical application to an eye of the patient.

6. The preparation according to claim 1, wherein the preparation is a liquid, semi liquid or solid formulation configured for systemic application to the patient.

7. The preparation according to claim 1, wherein the preparation further comprises at least one compound selected from the group consisting of vitamin B12, B6, B5, B2, B1, vitamin C, D, E, carotenoids, natural orange oil, and minerals.

8. The preparation according to claim 7, wherein the preparation further comprises at least one compound selected from the group consisting of selenium cholecalciferol, pantothenic acid vitamin B12, vitamin B6, vitamin B2, vitamin B1, zeaxanthine, lutein, vitamin E, vitamin C, copper salt, zinc salt, natural orange oil, and a sulfur compound.

9. The preparation according to claim 1, wherein the at least one folate in reduced form is selected from the group consisting of 5-methyl-(6S)-tetrahydrofolate, 5-formyl-(6S)-tetrahydrofolate, 5,10-methylene-(6R)-tetrahydrofolate, 5,10-methenyl-(6R)-tetrahydrofolate, 5-methyl-10-formyl-tetrahydrofolate, and 5-formyl-10-formyl-tetrahydrofolate and the folate salt is selected from calcium, sodium, zinc, arginine, choline, acetylcholine, N-methylaminoethanol, 2-amino-2-methyl-propanol, 1,1-dimethylbiguanidine, phenylethylbiguanidine, diaminoguanidine, glucosamine, and dimethylaminoethanol.

10. The preparation according to claim 1, wherein the preparation comprises a salt of the at least one folate in reduced form selected from the group consisting of 5-methyl-(6S)-tetrahydrofolate, 5-formyl-(6S)-tetrahydrofolate, in a range of 0.15 mg to 1.8 mg; and the preparation further comprises a sulfur compound or a salt thereof in a range of 28 mg to 350 mg; a selenium-compound in a range of 0.005 mg to 0.04 mg; cholecalciferol in a range of 0.009 mg to 0.06 mg; D-pantothenic acid in a range of 0.45 mg to 8 mg; vitamin B12 in a range of 0.003 mg to 0.98 mg; vitamin B6 in a range of 0.8 mg to 4 mg; riboflavin in a range of 2 mg to 14 mg; vitamin B1 in a range of 0.2 mg to 2 mg; zeaxanthine in a range of 1 mg to 3 mg; lutein in a range of 4 mg to 15 mg; vitamin E in a range of 1 mg to 8 mg; vitamin C in a range of 9 mg to 100 mg; natural orange oil in a range of 0.2 mg to 5.5 mg; copper in a range of 0.1 to 1 mg; and zinc in a range of 7 mg to 33 mg.

11. The preparation according to claim 1, wherein the preparation comprises a salt of the at least one folate in reduced form selected from the group consisting of 5-methyl-(6S)-tetrahydrofolate, 5-formyl-(6S)-tetrahydrofolate, in a range of 0.18 mg to 1.5 mg; sulfur compound or a salt thereof in a range of 29 mg to 316 mg; selenium in a range of 0.01 mg to 0.03 mg; cholecalciferol in a range of 0.015 mg to 0.045 mg; D-pantothenic acid in a range of 2 mg to 6 mg; vitamin B12 in a range of 0.005 mg to 0.6 mg; vitamin B6 in a range of 1.6 mg to 3.5 mg; riboflavin in a range of 3.7 mg to 10.5 mg vitamin B1 in a range of 0.45 mg to 1.6 mg zeaxanthine in a range of 1.9 mg to 2.1 mg; lutein in a range of 9 mg to 11 mg; vitamin E in a range of 2 mg to 6 mg; vitamin C in a range of 35 mg to 50 mg; natural orange oil in a range of 0.4 mg to 3.9 mg; copper in a range of 0.2 to 0.8 mg; and zinc in a range of 11 mg to 26 mg.

12. The preparation according to claim 1, wherein the preparation comprises a salt of the at least one folate in reduced form selected from the group consisting of 5-methyl-(6S)-tetrahydrofolate, 5-formyl-(6S)-tetrahydrofolate, in an amount of 0.9 mg; N-acetylcysteine or a salt thereof in an amount of 180 mg; selenium as L-selenomethionine in an amount of 0.02 mg; cholecalciferol in an amount of 0.0375 mg; pantothenic acid as calcium-D-pantothenate in an amount of 5 mg; methylcobalamin in an amount of 0.5 mg; pyridoxal-5′-phosphate in an amount of 3 mg; riboflavin in a n amount of 10 mg; thiamine mononitrate in an amount of 1.5 mg; zeaxanthine in an amount of 2 mg; lutein in an amount of 10 mg; D-α-tocopherol in an amount of 5 mg; calcium-ascorbate in an amount of 45 mg; natural orange oil; copper as copper-gluconate in an amount of 0.667 mg; and zinc as zinc oxide in an amount of 25 mg.

13. The preparation according to claim 1, wherein the preparation comprises a salt of the at least one folate in reduced form selected from the group consisting of 5-methyl-(6S)-tetrahydrofolate and 5-formyl-(6S)-tetrahydrofolate, in an amount of 0.6 mg; N-acetylcysteine or a salt thereof in an amount of 100 mg; selenium as L-selenomethionine in an amount of 0.02 mg; cholecalciferol in an amount of 0.02 mg; pantothenic acid as calcium-D-pantothenate in an amount of 3 mg; cyanocobalamin in an amount of 0.009 mg; pyridoxa1-5′-phosphate in an amount of 2.1 mg; riboflavin in an amount of 4.2 mg; thiamine mononitrate in an amount of 0.55 mg; zeaxanthine in an amount of 2 mg; lutein in an amount of 10 mg; D-α-tocopherol in an amount of 3 mg; calcium-ascorbate in an amount of 40 mg; natural orange oil; copper as copper-gluconate in an amount of 0.3 mg; and zinc as zinc oxide in an amount of 12.5 mg.

14. The preparation according to claim 1, wherein the preparation is in a form of a tablet, a hard gel capsule, or a soft gel capsule.

15. The preparation according to claim 1, wherein the preparation is in a form of a solution, a patch, an ointment, a cream, a lotion or an application for a controlled or sustained release.

16. A kit for use in reducing intraocular pressure, in a patient having an eye disease, the kit comprising at least 10 daily doses of a preparation comprising at least one folate in reduced form.

17. A method of reducing intraocular pressure in a patient having an eye disease, the method comprising administering to the patient a preparation comprising at least one folate in reduced form.

18. The method according to claim 17, wherein the eye disease is glaucoma, diabetic retinopathy, and/or age-related macular degeneration.

19. The method according claim 17, wherein the intraocular pressure is reduced below 20 mmHg.

20. The method according to claim 17, wherein the preparation is administered for at least 10 days.

21. The method according to claim 17, wherein the preparation is administered topically to an eye of the patient.

22. The method according to claim 17, wherein the preparation is administered systemically to the patient.

23. The method according to claim 17 wherein a dose of 0.2 mg to 100 mg per day of the at least one folate in reduced form is administered to the patient.

24. The preparation according to claim 8, wherein the preparation comprises at least one compound selected from the group consisting of L-selenomethionine, sodium selenite, sodium hydrogen selenite, sodium selenate, Dexpanthenol, calcium-D-pantothenate, sodium-D-pantothenate, methylcobalamin, cyanocobalamin, hydroxylcobalamin, adenosylcobalamin, pyridoxine hydrochloride, pyridoxal-5′-phosphate, sodium-riboflavin-5′-phophate, riboflavin, thiamine hydrochloride, thiamine mononitrate, D-α-tocopherol, DL-α-tocopherol, D-α-tocopherol, sodium-ascorbate, potassium-ascorbate, calcium-ascorbate, L-ascorbic acid, L-ascorbyl-6-palmitate, copper gluconate, copper citrate, copper oxide, copper lysine complex, zinc oxide, zinc gluconate, zinc lactate, zinc citrate, natural orange extract, limonene, myrcene, N-acetyl-cysteine, N-acetylcysteine amide, cysteine, lipoic acid, and methionine.

Description

EXAMPLE 1

[0064] A female patient suffering from pseudoexfoliate glaucoma (PEX) was examined on intraocular pressure on the occasion of two checks at the ophthalmologist. The first check was done on May 03, 2019 and revealed an intraocular pressure of 15 mm Hg (right eye) and 15 mm Hg (left eye). From first of May 2019 until 21 Aub. 2019 the patient took one capsule of Ocufolin® forte the composition of which is indicated below. On the second check of the intraocular pressure, taking place on 13 Aug. 2019, the measurement of the intraocular pressure gave the following results, 12 mm Hg (right eye) and 12 mm Hg (left eye).

[0065] The decrease of the intraocular pressure from 15 mm Hg to 12 mm Hg in the period of approximately 3 months of daily intake of Ocufolin® forte is a significant decrease, even more taking into account that an intraocular pressure of 15 mm Hg is in the range of 12 mm Hg to 20 mm Hg which is considered as normal. Ocufolin® forte is a preparation comprising L-5-Methyl-Folate, respectively its calcium salt. The composition, respectively the amount of its active ingredients is as indicated below. The compounds forming the capsule are not indicated.

TABLE-US-00001 Ocufolin ® forte Ingredient Per Capsule N-Acetylcysteine 180 mg Vitamin C (Ascorbic Acid) 45 mg Zinc (Zinc Oxide) 25 mg Vitamin B2 (Riboflavin) 10 mg Pantothenic acid (Ca-D-Pantothenate) 5 mg Vitamin E (natural Tocopherol) 5 mg Lutein 10 mg Vitamin B6 (Pyridoxa1-5-Phosphate) 3 mg Vitamin B1;Thiamine monontrate) 1.5 mg Calcium-L-Methylfolate (Folate, B9) 0.9 mg Zeaxanthine 2 mg Copper (Copper Gluconat) 0.667 mg Vitamin B12 (Methylcobalamin) 0.5 mg Vitamin D3 (Cholecalciferol) 37.5 mcg Selenium (L-Selenmethionine) 20 mcg

EXAMPLE 2

[0066] The following tables show the results of seven exemplary patients taking part in a study to assess the effect of a 3-month L-methylfolate containing preparation over 12 weeks (1 capsule per day) on intraocular pressure, total ocular blood flow and systemic homocysteine plasma concentration in patients with diabetes. The preparation comprising the at least one folate in reduced form which was used in this study is Ocufolin® forte. The composition is as indicated in example 1. Except that 25 mg of zinc were comprised in the form zinc acetate.

[0067] Systolic, diastolic and mean blood pressures (SBP, DBP, MAP) were measured on the upper arm by an automated oscillometric device. Pulse rate was automatically recorded from a finger pulse-oxymetric device.

[0068] Intraocular pressure was measured with a slit-lamp mounted Goldmann applanation tonometer. Before each measurement one drop of oxybuprocainhydrochloride combined with sodium fluorescein was used for local anesthesia of the cornea.

[0069] Fourier domain optical coherence tomography (FDOCT) was used to determine total ocular blood flow. It is based on a local phase analysis of the backscattered signal and allows for bidirectional Doppler flow imaging. It does not need reference arm scanning and records one full depth and Doppler profile in parallel. The system operates with an equivalent A-scan rate of 25 kHz and allows real time imaging of the color encoded Doppler information together with the tissue morphology at a rate of 2-4 tomograms (40×512 pixel) per second. Despite the high detection speed a system sensitivity of 86 dB using a beam power of 500 μW at the cornea is achieved. The fundus camera allowed simultaneous view for selection of the region of interest. Bi-directional blood flow and pulsatility of blood velocity in retinal vessels with a Doppler detection bandwidth of 12.5 kHz and a longitudinal velocity sensitivity in tissue of 200 μm/s was observed. Diffuse luminance flicker was applied during the measurements for 60 seconds.

[0070] Plasma homocysteine levels determination was done by the CMIA (chemiluminescent one step microparticle immunoassay) method (Shipchandler, M. T. and E. G. Moore, Rapid, fully automated measurement of plasma homocyst(e)ine with the Abbott IMx analyzer. Cl in Chem, 1995. 41(7): p. 991-4).

TABLE-US-00002 Subject Gender Height Weight Medical Date of Medical Date of Medical Date of Nr. Age (M/F) (cm) (kg) history onset history onset Ongoing history onset Ongoing  1 25 F 163  75 Diabetes NK/NK/00 Mellitus Type I  4 51 M 186  67 Diabetes NK/NK/71 Hypertension NK/NK/11 Yes Hypercholesterolemia NK/NK/11 Yes Mellitus Type I  9 38 M 188 108 Diabetes NK/NK/14 Lasik o.u. NK/NK/09 Yes Mellitus Type II 18 20 F 173  67 Diabetes Apr. 30, 2011 Mellitus Type I 19 55 F 157  68 Diabetes NK/NK/89 Mellitus Type II 23 56 M 183  85 Diabetes NK/NK/13 Arterial NK/NK/02 Yes Calf Cramps NK/NK/02 Yes Mellitus Hypertension Type II 25 42 M 180  80 Diabetes NK/NK/11 Mellitus Type II NK:Not Known

[0071] Day 1 represents the start of the study while Day 2 represents the time point in the study after supplementation for 12 weeks.

TABLE-US-00003 Blood pressure (mmHg) Subject Nr. Day 1 Day 2 1 124/089 125/082 4 115/063 121/067 9 135/094 137/096 18 120/074 130/075 19 114/075 117/074 23 123/083 120/075 25 136/082 132/083

TABLE-US-00004 Intraocular pressure of Intraocular pressure of the right eye (mmHg) the left eye (mmHg) Subject Nr. Day 1 Day 2 Day 1 Day 2 1 13 12 13 11 4 17 13 17 12 9 15 11 16 11 18 17 11 14 12 19 15 10 13 12 23 16 12 17 12 25 18 14 15 14

[0072] Only five of, seven subjects were tested on total ocular blood flow.

TABLE-US-00005 Total Ocular Blood Flow (μl/min) Subject Nr. Day 1 Day 2 1 37.7 38.4 4 — — 9 17.7 21.9 18 55.0 61.7 19 39.6 45.5 23 — — 25 33.2 38.9

TABLE-US-00006 Homocysteine (μmol/L) Subject Nr Day 1 Day 2 1 10.1 5.3 4 16.9 7.5 9 14.6 10.3 18 8.7 5.1 19 13.4 9.6 23 17.6 12.5 25 11.3 6.2