COMBINATIONS WITH 2-AMl ^' OETHANESULFONIC ACID

The present invention relates to the use of 2-aminoethanesulfonic acid in combination with a therapeutically active agent such as an antihypertensive agent.

2-aminoethanesulfonic acid (also known as tauric acid or taurine) is an unusual biological non-protein · -amino acid with a sulfonic acid group in place of the carboxyl group:

Though found in most tissues the endogenous production of 2-aminoethanesulfbnic acid is insufficient in humans and needs to be supplemented with food such as fish and meat. It crosses the blood-brain barrier and is described to have antioxidative properties, to regulate intracellular Ca \ to be involved in osmoregulation as an osmolyte, and to modulate in* ammatory reactions and neuronal activity. In cats 2-aminoethanesulfonic acid appears to be a trophic factor in the retina. In some pathological conditions including diabetes lowered tissue concentrations of 2-aminoethanesulfonic acid are found, and it has been reported that supplementation with 2-aminoethanesulfonic acid has the potential to attenuate said conditions.

With increasing age a large proportion of the adult population develops elevated blood pressure also referred to as "essential hypertension ^" , i.e. systolic blood pressure (SBP) higher than 120 mm Hg and diastolic blood pressure higher than 80 mm Hg. The hypertension leads to ventricular hypertrophy and is often combined with hyperlipidaemia. Both symptoms are serious risk factors for cardiovascular diseases leading to cardiovascular events such as myocardial infarction or stroke. Elevated blood cholesterol and lipid levels are involved in atherosclerosis, a condition characterized by unevenly distributed lipid deposits inside the arteries.

Different modes of anti-hypertensive action are known and a variety of different antihypertensive drags are available. Examples of such antihypertensive drugs are diuretics, calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs). Preferred embodiments of said examples are

• the diuretics hydrochlorothiazide and chlorthalidone,

• the CCBs amlodipine and nifedipine,

· the ARBs candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, and

• pharmaceutically acceptable salts thereof.

Diuretics reduce blood pressure by causing the kidneys to increase the amount of salt and water eliminated with the urine.

CCBs reduce blood pressure by interfering with the movement of Ca ²⁺ ions through voltage- gated calcium channels resulting in a decrease of intracellular calcium.

ARBs reduce blood pressure by blocking receptor sites of the peptide hormone angiotensin Π resulting in vasoconstriction and increased blood pressure. According to the present invention the bilirubin level in the blood of individuals with increased bilirubin levels (about 10% of the population) is decreased or lowered by supplementing their alimentation with 2-aminoethanesulfonic acid. In view of this surprising and unexpected finding individuals with an increased bilirubin level also benefit from treatment with a pharmaceutical preparation comprising 2-aminoethanesulfonic acid either alone or comprising an additional therapeutically active agent. Such a pharmaceutical preparation is particularly beneficial for an individual having one or two UGT1A1 *28 alleles such as an individual suffering from the Gilbert syndrome.

Additionally an unexpected increase of the thyroid stimulating hormone TSH (measured as tsh-basal) is observed. Such a TSH increase is known to result in stimulation of the thyroid gland to produce the thyroid hormones, which in turn increases the basal metabolic rate. In view of this surprising and unexpected finding, individuals suffering from a thyroid hormone imbalance benefit from 2-aminoethanesulfonic acid supplementation, which stabilizes their metabolic rate.

To reliably implement an individual's 2-aminoethanesulfonic acid intake it is desirable to combine the 2-aminoethanesulfonic acid with a therapeutic agent which the individual already takes daily. Examples of such therapeutic agents are antihypertensives, antidiabetics and lipid lowering agents. Particularly preferred are antihypertensives.

Antihypertensive treatment, i.e. reduction of elevated blood pressure, has been shown to result in various clinical benefits such as reductions in cardiovascular mortality and morbidity, stroke, and the incidence of dementia. However, in a high proportion of patients treatment with a single active agent does not suffice to reach the target blood pressures of SBP below 140 mm Hg and DBP below 90 mm Hg, which in the case of patients additionally diagnosed for diabetes should even be SBP below 130 mm Hg and DBP below 80 mm Hg. Therefore, said patients need to be treated with a combination of two or three different antihypertensive agents to reach their beneficial target blood pressures.

Though 2-aminoethanesu!fonic acid alone i reported to exert an antihypertensive effect it has not been recognized that the antihypertensive effect of treatment with a diuretic, calcium channel blocker or angiotensin receptor blocker can be further increased by combining said treatment with a 2-aminoethancsul onic acid treatment. The present invention for the first time teaches, that daily blood pressure treatment with a diuretic, a CCB or an ARB combined with a 2-aminoethanesulfonie acid treatment can result in an additional or synergistic blood pressure reduction as compared to treatment with the antihypertensive diuretic, CCB or ARB alone. Simultaneously the homeostatic properties associated with 2-aminoethanesulfonic acid stabilize the reduced blood pressure over the 24 hour treatment period and reduce the incidence of a number of adverse events such as hypotension, syncope or arrhythmia. While 2 -ami noet hane su 1 fonic acid can be administered separately, administration of the

antihypertensive and 2-aminoethanesulfonic acid in a single dosage form improves patient compliance and, thus, insures that a blood pressure patient takes advantage of the additional benefits associated with 2-aminoethanesulfonic acid treatment. 2-aminoethanesulfonic acid represents an endogenously produced component of blood pressure regulation and is not a customary antihypertensive agent. Therefore, using a therapeutic combination of an antihypertensive agent with 2-aminoethanesulfonic acid has the additional advantage, that no or less additional anti-hypertensive agent is needed to achieve the beneficial target blood pressure. Additionally, the effect on the thyroid hormones stabilizes the patient ^' s metabolic rate. In individuals with increased bilirubin levels said level is unexpectedly decreased. Thus, hypertensive individuals with an increased bilirubin level additionally benefit from treatment with 2-aminoethanesulfonic acid.

Further benefits of combining a diuretic, CCB or ARB with 2-aminoethanesulfonic acid are

• increased generation of the vasodilator NO;

• increase of intracellular Ca ²⁺ concentrations to maintain calcium homeostasis;

• decreased LOX- 1 expression;

• decreased serum concentration of C-reactive protein (CRP);

· membrane stabilization and mitigated development of arterial stiffness, improved vascular relaxation, endothelial apoptosis, oxidative stress and inflammation particularly in diabetic patients;

• improved lipid metabolism particularly in overweight individuals resulting in reduced serum cholesterol, reduced triglyceride or even reduced body weight;

· improved sleep;

• decreased atherogenic index;

• reduced blood platelet aggregation;

• prevention of the formation of advanced glycation end products (AGE);

• protective effects against renal damage, cataracts and glaucoma; and

· neuroprotection for example with respect to Alzheimer's, disease.

Beneficial effects are not only observed in the treatment of hypertension but also in the treatment of conditions such as congestive heart failure, hypercholesterolemia, retinal disorders, neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease and hepatic problems such as the Gilbert Syndrome.

Thus, 2-aminoethanesulfonic acid cooperates favourably with an antihypertensive diuretic, calcium channel blocker or ARB, for example, in the treatment or prevention of congestive heart failure, cardiovascular disease, stroke, transient ischemic attack, myocardial infarction, dyslipidemia, cognitive decline or dementia.

About 10% of the population are affected by the Gilbert Syndrome, i.e. a mutation in the UGTl Al gene (UGTl Al *28). This means that about 10% o the hypertensive patients also have reduced bilirubin conjugation and unconjugated hyperbilirubinemia. In these patients 2- aminoethanesulfonic acid accelerates biliary excretion of bilirubin providing neuroprotection against bilirubin-induccd elevation of apoptosis and intracellular free Ca ^÷ , Additionally, the added 2-aminoethanesulfonic acid supports the prevention of gallstone fonnation. Despite the increased excretion of bilirubin, which has favourable anti oxidative properties, the anioxidative potential is maintained by the antioxidative properties of 2-aminoethanesulfonic acid. Thus, the present invention for the first time recognizes that low cancer mortality, found associated with elevated bilirubin levels, should be advantageously maintained by supplemented 2-aminoethanesulfonic acid.

Object of the present invention is to provide an oral pharmaceutical preparation comprising 2- aminoethanesulfonic acid and an antihypertensive agent selected from the group consisting of a diuretic, a calcium channel blocker (CCB), or an angiotensin receptor blocker (ARB) including a pharmaceutically acceptable salt thereof. Optimized combinations consist of the two ingredients in admixture with one or more cxcipients (adjuvants). Particularly preferred preparations are capsule, tablet or effervescent tablet dosage forms. Tablets may comprise a single, two or more layers.

2-aminoethanesulfonic acid also favourably cooperates with a thercapcutically active (in particular antipsychotic, antidepressant, antiplatelet, antidiabetic or antihypei ipidemic) agent such as olanzapine (about 2.5-20 mg), pramipexole (0.1 -1 mg), ropinirol (0.5-4 mg), duloxetine (about 20-60 mg), cscitalopram (about 4-8 mg), risperidone (about 0.25-4 mg), clopidogrel (about 75 mg), sitagliptin (about 25-100 mg), fenofibrate (about 40- 120 mg) or benzafibrat (about 200 mg). Preferably, 2-aminoethanesulfonic acid is combined with an active agent, the metabolism of which does not rely on the UGT 1 A 1 encoded gene product.

Examples of suitable excipients (adjuvants) are mannitol, sorbitol, xylit, saccharose, calciumcarbonat, calciumphosphat, lactose, croscarmellose sodium salt (cellulose

carboxymethylcthcr sodium salt, cross linked), crospovidone, sodium starch glycolate, hydroxypropylcellulose (low substituted), maize starch, polyvinylpyrrolidon, copolymers of vinylpyrrolidon with other vinylderivatives (copovidones), hydroxypropyl cellulose, hydroxypropylmethyl cellulose, microcristalline cellulose or starch, magnesiumstearat, sodiumsteaiylfuinarat, talc, hydroxypropylmethyleellulose, carboxyniethylcellulose, celluloseacetatphthalat, polwinylacctat. water, water/ethanol, water/glycerine, water/sorbit, w atcr po 1 y ethyl eng 1 y ko 1 , propylenglykol, cetylstearyl lkohol, carboxymethylcellulose or substances containing fat such as hard grease.

Various excipients are usually included for different purposes:

• Mannitol, sorbitol, xylit, saccharose, calciumcarbonat, calciumphosphat and lactose are examples of inert diluents;

· croscarmellose sodium salt (cellulose earboxymethylethcr sodium salt, cross linked), crospovidone, sodium starch giycolate, hydroxypropylcellulose (low substituted) and maize starch are examples of disintegrants, sodium starch giycolate being preferred;

• polyvinylpyrrolidon, copolymers of vinylpyrrolidon with other vinylderivativcs

(copovidones), hydroxypropyl cellulose, hydroxypropylmethyl cellulose, microcristalline cellulose or starch are binders;

• magnesiumstcarat, sodiumstearylfumarat and talc have the function of lubricants;

• examples for agents delaying release are hydroxypropylmethyl cellulose, carboxymelhyl cellulose, celluloseacetatphthalat and polyvinyl acetate; and

• ferric oxides are dyes acceptable for pharmaceutically use.

Preferred embodiments of the present invention are pharmaceutical preparations, wherein the antihypertensive agent is selected from the group consisting of hydrochlorothiazide, chlorthalidone, amlodipine, nifedipine, telmisartan, irbesartan, valsartan, candesartan, losartan, olmesartan, azilsartan or a pharmaceutically acceptable salt thereof.

Examples of preferred pharmaceutical preparations comprise chlorthalidone,

hydrochlorothiazide or amlodipine or a pharmaceutically acceptable salt thereof such as amlodipine besylate. Particularly preferred is a pharmaceutical preparation, wherein the angiotensin receptor blocker is telmisartan or the sodium or calcium salt thereof. In a preferred embodiment the capsule or tablet comprises 2-aminoethanesulfonic acid and telmisartan or a pharmaceutically acceptable salt thereof together with the excipients sorbitol and magnesium stearate, compressed directly into tablets. In a particularly preferred embodiment the excipient is selected from the group consisting of mannitol, sorbitol, xylit, saccharose, calciumcarbonat, calciumphosphat, lactose,

croscarmellose sodium salt (cellulose carboxymethylether sodium salt, cross linked), crospovidone, sodium starch glycolate, Hydroxypropylcellulose (low substituted), maize starch, po lyvi ny 1 pyrro 1 i don, copolymers of vinylpyiTolidon with other vinylderivatives (copovidones), hydroxypropyl cellulose, hydroxypropylmethyl cellulose, microcristalline cellulose or starch, magnesiumstearat, sodiumsteaiylfumarat, talc,

hydroxypropylmethylcellulose, carboxymethylccllulose, cclluloseacetatphthalat,

polyvinylacetat, water, water/ethanol, water/glycerine, water/sorbit, water/polyethylenglykol, propylenglykol, cetylstearylalkohol, carboxymethylccllulose or substances containing fat.

The amount of diuretic in a single dosage form is usually in the range of 10-50 mg of the diuretic such as HCTZ or chlorthalidone.

The amount of CCB in a single dosage form is usually in the range of a 1 -100 mg of CCB such as 5- 10 mg f amlodipine or 10-90 mg of nifedipine.

The amount of ARB in a single dosage form is usually in the range of 10-800 mg, depending on the ARB used. Preferred ranges arc 150-300 mg (e.g. irbesartan), 60-90 mg (e.g. valsartan or telmisartan), 20-90 mg (e.g. telmisartan or losartan) or 15-30 mg (e.g. candesartan).

Particularly preferred are 80-85 mg, 40-45 mg or 20-25 mg.

The amount of 2-aminoethanesulfonic acid in a single dosage form is usually in the range of 250-1000 mg and the weight ratio of 2-aminoethanesulfonic acid to, for example, telmisartan or a polymorph or salt thereof is in the range of 25: 1 to 5: 1.

Thus, tablets according to the present invention can contain 20-200 mg, preferably 60-90 mg or 30-60 mg telmisartan or its sodium salt, and 300-600 mg, 2-aminoethanesulfonic acid. Particularly preferred are amounts of 80-85 mg or 40-45 mg telniisartan or its sodium salt and 250 nig or 500 mg 2-aminoethanesulfonic acid.

In said tablets 2-aminoethanesulfonic acid can be additionally combined with a diuretic such as 10-50 mg HCTZ or chlorthalidone, or a CCB such as 5-10 mg amlodipine.

Another embodiment of the present invention is a method of producing an oral capsule or tablet or effervescent tablet dosage form comprising mixing 2-aminocthanesulfonic acid and an antihypertensive agent selected from the group consisting of a diuretic, a calcium channel blocker, and an angiotensin receptor blocker with one or more pharmaceutically acceptable excipicnts.

The specific preparations according to the present invention are used to treat hypertension in a mammal while implicating a number of unexpected therapeutic benefits such as

· increased generation of NO and intracellular Ca ²⁺ concentrations;

• improved lipid metabolism and sleep; and

• mitigated arterial stiffness;

• protective effects against renal damage, retinal disorders, cataract, glaucoma; congestive heart failure, hypercholesterolemia, hepatic problems and Alzheimer ^' s disease,

Therefore, the preparations according to the invention can be used to additionally treat or prevent cardiovascular events, left ventricular hypertrophy, stroke, cardiac insufficiency (heart failure), myocardial infarction, diabetic nephropathy or diabetic retinopathy. In particular they additionally reduce the risk of transient ischemic attacks, stroke, myocardial infarction, progression of cardiac insufficiency after cardiovascular events selected from the group consisting of myocardial infarction, left ventricular hypertrophy, diabetic nephropathy or retinopathy, and any kind of cardiovascular death.

In a preferred embodiment preparations of the present invention are used to treat human patients in whom the prevention or treatment of cardiovascular, cardiopulmonary or renal diseases is indicated or carrying the UGT1 Al *28 mutation, with a preparation comprising a diuretic. CCB or an ARB such as telmisartan in combination with 2-aminoethanesulfonic acid optionally with one or more excipients. By combining an antihypertensive agent such as a diuretic, a CCB or and ARB with

2-aminoethanesulfonic acid an additional reduction in systolic and diastolic blood pressure is achieved. This is even more beneficial taking into account the additional therapeutic and preventive benefits due to the combination with 2-aminoethanesulfonic acid such as

• increased generation of NO and intracellular Ca ²⁺ concentrations;

• improved lipid metabolism with decreased atherogenic index; and

• mitigated development of arterial stiffness, oxidative stress and inflammation. To produce a pharmaceutical preparation for oral administration according to the invention procedures known in the art can be used. Suitable excipients for the compression of diuretics, CCBs or ARBs with 2-aminoethanesulfonic acid after mixing are sorbitol and

magnesiumstearat, which can be replaced by other excipients such as mannitol or saccharose. Occasionally the properties of tablets can be modified by granulation of the antihypertensive agent or 2-aminoethanesulfonic acid or both with selected excipients before final compression of all the components of the pharmaceutical preparation. For this purpose the diuretic, CCB, ARB or salt thereof is mixed, for example, with mannitol, hydroxypropyl cellulose and, optionally, a colouring agent in a suitable blender. The resulting blend is preferably sieved and can be subjected to a dry granulation process in a roller compactor. The mentioned excipients might be replaced by other adjuvants such as lactose or microcristalline cellulose. The resulting granulate can be mixed with 2-aminoethanesulfonic acid and other excipients such as mannitol, microcristalline cellulose, sodium starch glycolate, magnesium stearate and optionally a colouring agent before being compressed to tablets. Alternatively, adjuvants such as lactose or erosearmellose sodium salt can be used.

It is preferred that the dosage form comprising a diuretic, CCB or ARB and 2-aminoethanesulfonic acid has fast dissolution and immediate drug release properties combined with adequate stability. In case mere combination of the active ingredients is not practical due to incompatibilities with excipients used in the mono-dosage form of the active ingredients, it is possible to coat 2-aminoethanesulfonic acid particles in a fluidized-bed granulator with a polymer solution containing water soluble polymers like hydroxypropyl-cellulosc, hydroxypropyl methylcellulose or polyvinylpyrrolidone, thereby reducing the contact surface area of the 2-aniinoethanesulfonic acid particles with the other components of the dosage form.

The dissolving tablet matrix may have acidic, neutral or basic properties. For the ARB tehnisartan for example a basic tablet matrix is preferred. In this embodiment, the dissolving matrix comprises a basic agent, a water-soluble diluent and, optionally, other excipients (adjuvants). Specific examples of suitable basic agents are alkali metal hydroxides such as NaOH and KOH; basic amino acids such as arginine and lysine; and meglumine (N-methyl- D-glucamine). NaOH and meglumine being preferred.

Other (optional ) constituents may, for instance, be chosen from one or more of the following excipients and/or adjuvants in the amounts indicated:

10 to 30 wt. %, preferably 15 to 25 wt. %, of binders, earners and fillers, thereby replacing the water-soluble diluents;

0.1 to 5 wt. %, preferably 0.5 to 3 wt. %, of lubricants;

0.1 to 5 wt. %, preferably 0.3 to 2 wt. %, of flow control agents;

1 to 10 wt. %, preferably 2 to 8 wt. %, of crystallization retarders;

1 to 10 wt. %, preferably 2 to 8 wt. %, of solubilizers;

0.05 To 1 .5 wt. %, preferably 0.1 to 0,8 wt. %, of colouring agents;

0.5 to 10 wt. %, preferably 2 to 8 wt. %, of pH control agents;

0.01 to 5 wt. %, preferably 0.05 to 1 wt. %, of surfactants and emulsifiers.

The tablets prepared release the diuretic, CCB or ARB and 2-aminoethanesulfonic acid rapidly and in a largely pH-independent fashion, with complete release occurring within less than 90 min and release of the major fraction occurring within less than 30 min.

The following examples illustrate the subject matter of the invention. Example 1 : 40 mg teimisartan and 250 mg 2-aminoethane-sulfonic acid tablet mg %

Constituents per tablet per tablet

Teimisartan 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 Teimisartan layer 475.000 100.000

Example 2: 40 mg teimisartan and 500 mg 2-aminoethanesulfonic acid tablet

mg %

Constituents per tablet per tablet

Teimisartan 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 Teimisartan layer 700.000 100.000 Example 3: 40 mg teimisartan and 500 mg 2-aminoethanesulfonic acid capsule

mg %

Constituents per capsule per capsule

Teimisartan 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 1 1 .286

Magnesium stearate 1.000 0.143

Total Teimisartan layer 700.000 100.000

- I I - Example 4: 5 mg amlodipine and 250 mg 2-aminoethane-sulfonic acid tablet 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 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

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 mg %

Constituents per tablet per tablet

Taurine 250.000 55.556

Hydrochlorothiazide (HCTZ) 12.500 2.778

Lactose mo no hydrate 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

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

mg %

Constituents per tablet per tablet

Hydrochlorothiazide (HCTZ) 12.500 2.778

Taurine 250.000 55.556

Lactose monohydrate 1 12.500 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 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 1 1 : 20 mg telmisartan, 5 mg amlodipine, 12.5 mg HCTZ and 250 mg 2- aminoethane-sulfonic acid tablet

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

The last three columns of Table 1 show hcmograra parameters compiled on different dates for an individual later diagnosed to carry in the promoter region of both UGT 1 A 1 alleles 7 ΤΛ- repeats instead of 6 TA-repeats corresponding to the genotype UGTlAl*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.

Tablei P a Γ m P†P analysis 1 of analysis 2 of analysis 3 of

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

LDI . -cholesterol mg/dl 107 97 82

glucose mg/dl 84 93 87

ferritin μ /l 179 197

erythrocytes Μιο/μΐ 5 5, 1 4,8

haemoglobin g dl 14, 1 14.5 14,3

hematocrit 1/1 0,4 0,42

CV fL 85 78,3 88,7

MCH pg 28 28 30

MCHC g/dl 33 36 34

thrombocytes /nl 193 229 193

tsh basal μυ/ml 1 , 19 1 ,2 1 ,38

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.

Table 2

average of analysis of Difference /

Parameter Unit

analysis 1 to 3 March 2013 %

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-eholesterol mg/dl 95,3 100 5

glucose mg/dl 88,0 84 -5

ferritin μ /1 188,0 137 -27

erythrocytes Mio/μΙ 5,0 5,08 2

haemoglobin g/dl 14,3 14,6 2 hematocrit 1/1 0,4 0,442 7

MCV 11 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 • μυ/ml 1,3 2,29 82

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.

For a person skilled in the art these changes are unexpected and suprising, In particular the decrease of the total bilirubin value despite the patient ^' s UGT1 A 1 *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 mg %

Constituents per tablet per tablet

Olanzapine 5 1.25

Taurine 250 62.50

icrocrystalline 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-suifonic acid tablet 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