Combinations with 2-aminoethanesulfonic acid

Abstract

The invention relates to a pharmaceutical combination of 2-aminoethanesulfonic acid with a pharmaceutical agent such as an antihypertensive agent and the use of 2-aminoethanesulfonic acid in a method to lower the bilirubin level in the blood.

Claims

1. A pharmaceutical preparation for oral administration comprising 250-1000 mg 2-aminoethanesulfonic acid and an antihypertensive agent selected from the group consisting of telmisartan, irbesartan, valsartan, olmesartan, and azilsartan or a pharmaceutically acceptable salt thereof in admixture with one or more excipients selected from the group consisting of mannitol, sorbitol, xylitol, saccharose, calcium carbonate, calcium phosphate, lactose, croscarmellose sodium salt, crospovidone, sodium starch glycolate, hydroxypropylcellulose (low substituted), maize starch, polyvinylpyrrolidone, copolymers of vinylpyrrolidone with other vinyl derivatives, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose or starch, magnesium stearate, sodium stearyl fumarate, talc, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, polyvinylacetate, water, water/ethanol, water/glycerine, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or substance containing fat.

2. The preparation according to claim 1, characterized in that the preparation contains 20-200 mg of the angiotensin blocker telmisartan.

3. The preparation according to claim 1, wherein the preparation is effective to lower the bilirubin level of a hypertensive individual having unconjugated hyperbilirubinemia.

4. The preparation according to claim 3, wherein the preparation is effective to lower the bilirubin level of a hypertensive individual with an UGT1A1*28 allele.

5. The preparation according to claim 1 wherein the antihypertensive agent is irbesartan.

6. The preparation according to claim 1 wherein the antihypertensive agent is valsartan.

7. The preparation according to claim 1 wherein the antihypertensive agent is olmesartan.

Description

EXAMPLE 1

40 mg Telmisartan and 250 mg 2-aminoethane-sulfonic Acid Tablet

(1) TABLE-US-00001 mg % Constituents per tablet per tablet Telmisartan 40.000 8.421 Taurine 250.000 52.632 Sodium hydroxide 3.360 0.707 Meglumine 12.000 2.526 Povidone 12.000 2.526 Sorbitol 150.640 31.714 Magnesium stearate 7.000 1.474 Total Telmisartan layer 475.000 100.000

EXAMPLE 2

40 mg Telmisartan and 500 mg 2-aminoethanesulfonic Acid Tablet

(2) TABLE-US-00002 mg % Constituents per tablet per tablet Telmisartan 40.000 5.714 Taurine 500.000 71.429 Sodium hydroxide 3.360 0.480 Meglumine 12.000 1.714 Povidone 12.000 1.714 Sorbitol 125.640 17.949 Magnesium stearate 7.000 1.000 Total Telmisartan layer 700.000 100.000

EXAMPLE 3

40 mg Telmisartan and 500 mg 2-aminoethanesulfonic Acid Capsule

(3) TABLE-US-00003 mg % Constituents per capsule per capsule Telmisartan 40.000 5.714 Taurine 500.000 71.429 Meglumine 40.000 5.714 Crystalline cellulose 20.000 2.857 Poloxamer 188 8.000 1.143 Povidone 12.000 1.714 D-mannitol 79.000 11.286 Magnesium stearate 1.000 0.143 Total Telmisartan layer 700.000 100.000

EXAMPLE 4

5 mg Amlodipine and 250 mg 2-aminoethane-sulfonic Acid Tablet

(4) TABLE-US-00004 mg % Constituents per tablet per tablet Amlodipine besylate 6.944 1.543 Taurine 250.000 55.556 Microcrystalline cellulose 100.000 22.222 Dibasic calcium phosphate 85.556 19.012 Sodium starch glycolate 6.000 1.333 Magnesium stearate 1.500 0.333 Total Telmisartan layer 450.000 100.000

EXAMPLE 5

5 mg Amlodipine and 500 mg 2-aminoethanesulfonic Acid Tablet

(5) TABLE-US-00005 mg % Constituents per tablet per tablet Amlodipine besylate 6.944 0.992 Taurine 500.000 71.729 Microcrystalline cellulose 100.000 14.286 Dibasic calcium phosphate 85.556 12.222 Sodium starch glycolate 6.000 0.857 Magnesium stearate 1.500 0.214 Total Telmisartan layer 700.000 100.000

EXAMPLE 6

10 mg Amlodipine and 500 mg 2-aminoethanesulfonic Acid Capsule

(6) TABLE-US-00006 mg % Constituents per capsule per capsule Amlodipine besylate 12.840 1.427 Taurine 500.000 55.556 Microcrystalline cellulose 200.000 22.222 Pregelatinized starch 171.160 19.018 Sodium starch glycolate 12.000 1.333 Colloidal silicon dioxide 2.000 0.222 Magnesium stearate 2.000 0.222 Total Telmisartan layer 900.000 100.000

EXAMPLE 7

12.5 mg HCTZ and 250 mg 2-aminoethane-sulfonic Acid Tablet

(7) TABLE-US-00007 mg % Constituents per tablet per tablet Taurine 250.000 55.556 Hydrochlorothiazide (HCTZ) 12.500 2.778 Lactose monohydrate 112.500 25.000 Microcrystalline cellulose 64.000 14.222 Corn starch 6.000 1.333 Sodium starch glycolate 4.000 0.889 Magnesium stearate 1.000 0.222 Total Telmisartan layer 450.000 100.000

EXAMPLE 8

25.0 mg HCTZ and 250 mg 2-aminoethane-sulfonic Acid Tablet

(8) TABLE-US-00008 mg % Constituents per tablet per tablet Taurine 250.000 55.556 Hydrochlorothiazide (HCTZ) 25.000 2.778 Lactose monohydrate 100.000 25.000 Microcrystalline cellulose 64.000 14.222 Corn starch 6.000 1.333 Sodium starch glycolate 4.000 0.889 Magnesium stearate 1.000 0.222 Total Telmisartan layer 450.000 100.000

EXAMPLE 9

12.5 mg HCTZ and 500 mg 2-aminoethane-sulfonic Acid Tablet

(9) TABLE-US-00009 mg % Constituents per tablet per tablet Hydrochlorothiazide (HCTZ) 12.500 2.778 Taurine 250.000 55.556 Lactose monohydrate 112.500 25.000 Microcrystalline cellulose 64.000 14.222 Corn starch 6.000 1.333 Sodium starch glycolate 4.000 0.889 Magnesium stearate 1.000 0.222 Total Telmisartan layer 700.000 100.000

EXAMPLE 10

20 mg Telmisartan and 250 mg 2-aminoethane-sulfonic Acid Tablet

(10) TABLE-US-00010 mg % Constituents per tablet per tablet Telmisartan 20.000 4.444 Taurine 250.000 55.556 Sodium hydroxide 1.680 0.373 Meglumine 12.000 2.667 Povidone 12.000 2.667 Sorbitol 147.320 32.738 Magnesium stearate 7.000 1.556 Total Telmisartan layer 450.000 100.000

EXAMPLE 11

20 mg Telmisartan, 5 mg Amlodipine, 12.5 mg HCTZ and 250 mg 2-aminoethane-sulfonic Acid Tablet

(11) TABLE-US-00011 mg % Constituents per tablet per tablet Telmisartan 20.000 4.000 Amlodipine besylate 6.944 1.389 Hydrochlorothiazide (HCTZ) 12.500 2.500 Taurine 250.000 52.632 Sodium hydroxide 1.680 0.336 Meglumine 12.000 2.400 Povidone 12.000 2.400 Sorbitol 177.876 35.575 Magnesium stearate 7.000 1.400 Total Telmisartan layer 500.000 100.000

EXAMPLE 12

Effect of Treatment with 2-aminomethanesulfonic Acid

(12) The last three columns of Table 1 show hemogram parameters compiled on different dates for an individual later diagnosed to carry in the promoter region of both UGT1A1 alleles 7 TA-repeats instead of 6 TA-repeats corresponding to the genotype UGT1A1*28/*28. This is in line with the increased values for total bilirubin, which should normally be in the range of 0.2 to 1.2 mg/dl. The individual did not receive any treatment.

(13) TABLE-US-00012 TABLE 1 analysis 1 of analysis 2 of analysis 3 of Parameter Unit March 2006 January 2009 March 2011 Total Bilirubin mg/dl 2.4 2.3 creatinin mg/dl 1.1 0.9 0.89 Uric acid mg/dl 5.1 4.1 4.7 triglyceride mg/dl 65 70 56 Total cholesterol mg/dl 176 177 174 HDL-cholesterol mg/dl 68 61 80 LDL-cholesterol mg/dl 107 97 82 glucose mg/dl 84 93 87 ferritin g/l 179 197 erythrocytes Mio/l 5 5.1 4.8 haemoglobin g/dl 14.1 14.5 14.3 hematocrit l/l 0.42 0.4 0.42 MCV fL 85 78.3 88.7 MCH pg 28 28 30 MCHC g/dl 33 36 34 thrombocytes /nl 193 229 193 tsh basal U/ml 1.19 1.2 1.38

(14) The third column of Table 2 shows the average values of the three hemograms of Table 1 while the fourth column shows the parameters compiled on a day after the individual has been daily treated for at least 3 months with 400 to 500 mg of 2-aminomethanesulfonic acid. The fifth column calculates the difference of the values in the forth and third column in % of the value in the third column. Thus, the fifth column describes the change of the value in the third column caused by the individual's treatment with 2-aminomethanesulfonic acid.

(15) TABLE-US-00013 TABLE 2 average of analysis of Parameter Unit analysis 1 to 3 March 2013 Difference/% total Bilirubin mg/dl 2.4 1.35 43 creatinin mg/dl 1.0 0.94 6 Uric acid mg/dl 4.6 4.01 13 triglyceride mg/dl 63.7 39 39 total cholesterol mg/dl 175.7 188 7 HDL-cholesterol mg/dl 69.7 78 12 LDL-cholesterol mg/dl 95.3 100 5 glucose mg/dl 88.0 84 5 ferritin g/l 188.0 137 27 erythrocytes Mio/l 5.0 5.08 2 haemoglobin g/dl 14.3 14.6 2 hematocrit l/l 0.4 0.442 7 MCV fL 84.0 87 4 MCH pg 28.7 29 1 MCHC g/dl 34.3 33 4 thrombocytes /nl 205.0 184 10 tsh basal U/ml 1.3 2.29 82

(16) The treatment with 2-aminomethanesulfonic acid causes a more than 40% decrease of the total bilirubin value; an almost 40% decrease in the triglyceride value; a more than 25% reduction of the ferritin value; and a more than 80% increase in the basal tsh value.

(17) For a person skilled in the art these changes are unexpected and surprising. In particular the decrease of the total bilirubin value despite the patient's UGT1A1*28/*28 genotype appears puzzling as does the highly significant increase of the tsh basal value which is highly relevant for the activity of the thyroid gland and the basal metabolic rate.

EXAMPLE 13

5 mg Olanzapine and 250 mg 2-aminoethane-sulfonic Acid Tablet

(18) TABLE-US-00014 mg % Constituents per tablet per tablet Olanzapine 5 1.25 Taurine 250 62.50 Microcrystalline cellulose 25 6.25 Mannitol 10 2.50 Povidone 10 2.50 Sorbitol 98 24.50 Magnesium stearate 2 0.50 Total Olanzapine layer 400 100.00

EXAMPLE 14

80 mg Fenofibrate and 250 mg 2-aminoethane-sulfonic Acid Tablet

(19) TABLE-US-00015 mg % Constituents per tablet per tablet Fenofibrate 80 20.00 Taurine 250 62.50 Microcrystalline cellulose 28 7.00 Mannitol 10 2.50 Povidone 10 2.50 Pregelatinized atarch 20 5.00 Magnesium stearate 2 0.50 Total Fenofibrate layer 400 100.00