WO2011002425A2

WO2011002425A2 - Pharmaceutical composition increasing solubility and stability

Info

Publication number: WO2011002425A2
Application number: PCT/TR2010/000126
Authority: WO
Inventors: Bilgig Mahmut
Original assignee: Bilgig Mahmut
Priority date: 2009-07-02
Filing date: 2010-06-25
Publication date: 2011-01-06
Also published as: EP2448575A2; WO2011002425A3

Abstract

The present invention is about pharmaceutical compositions having problems of solubility and stability, the preparation method of these compositions and the medical use.

Description

PHARMACEUTICAL COMPOSITION INCREASING SOLUBILITY AND STABILITY

Field of the Invention

The present invention relates to pharmaceutical compositions having problems of solubility and stability and the medical use and the preparation method of these compositions.

Background of the Invention

The present invention provides a combination which is effective in the treatment of essential hypertension. This effect provided by a combination in accordance with the invention is named as "desired effect" during the patent. Defined combination comprises telmisartan as an antihypertensive agent and hydrochlorothiazide (HCTZ) as a thiazide derivative diuretic.

Hypertension is the condition in which the blood pressure is higher than normal values. (Table

1).

Table 1.

Classification of blood pressure of adults aged 18 and plus

Hypertension can be classified as essential (primer) or secondary hypertension. Hypertension which is not related to any known medical reason is named as essential hypertension; the elevation of blood pressure caused by another reason as renal desease and tumors is named as secondary hypertension.

Pathophysiology of essential hypertension has not been well understood. Apparently, cardiac flow rate increases at early stage of the disease, but total peripheric resistance (TPR) is normal. In time, cardiac flow rate drop to normal levels, but this time, TPR increases. To explain this condition, three theories are produced;

Due to the kidney insufficiency in sodium elimination, the secretion of natriuretic factors as Atrial Natriuretic Factor to increase salt elimination and the elevation of total peripheric resistance as side effect

Due to the high activity of renin-angiotensin system, the involvement of sodium and water, the formation of vasoconstriction and the formation of hypertension related to the increase of blood volume.

Due to the high activity of sympathetic nervous system, the elevation of stress response. Besides, hypertension is known to be a hereditary disease in high percentage.

Hypertension is a serious disease and without treatment, consequences can reach to life- threatening sizes. Hypertension without treatment is an important risk factor for the disease as cerebrovascular accident (paralysis), miocard infarct (heart attack), hypertensive cardiomiopathie (congestive heart failure), cardiac dilatation, heartbeat disorder, atherosclerosis which can cause ischemic heart disease, coronary arterial disease, arterial aneurism, hypertensive retinopathy (retina damage), hypertensive nephropathy (chronical kidney failure), hypertensive encephalopathy (confusion, headache, convulsion), bleeding in brain blood vessel and thrombosis.

The best method suitably proved in the treatment of essential hypertension is the inhibition of the renin-angiotensin system. Drugs used for this reason are angiotensin II receptor antagonists such as telmisartan. Another drug group proved to being effective to control hypertension is diuretics which increase the activity of angiotensin II receptor antagonists.

Chemical name of telmisartan is 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazole]-r- yl)methyl]-[l,r-bifenyl]-2-carboxylic acid. (Formula 1).

Telmisartan is firstly described in the patent numbered EP502314 Bl (In patent family, patents numbered EP0552765 Bl, US5591762 A, US5594003 A, US5602127 A and US5614519 A are included). In the patent, processes for preparing telmisartan, pharmaceutical compositions comprising telmisartan and angiotensin antagonist activity of telmisartan are also situated.

Telmisartan is a strong, long acting and non-peptide angiotensin II receptor antagonist and it is used in the treatment of hypertension. Angiotensin II is synthesized from angiotensin I with a reaction catalyzed by angiotensin converting enzyme (ACE). Angiotensin II has effects as vasoconstriction, excitation of aldosterone synthesis and secretion, cardiac excitation and the enhancement of sodium back absorption from kidney tubulus. Telmisartan inhibits effects of angiotensin II by selectively blocking binding to ATI receptor in many tissues as vascular smooth muscle and adrenal gland. For this reason, mechanism of action of telmisartan is independent from routes wherein synthesis of angiotensin II occurs. Besides, AT2 receptors are found in many tissues. However, it is not known that AT2 receptor is related to cardiovascular homeostasy. The ATI receptor affinity of telmisartan is more than its AT2 receptor affinity. HCTZ is a thiazide derivative diuretic with a chemical name of 6-chloro-3, 4-dihydro-2H- 1,2,4- benzothiadiazine-7-sulfonamide 1,1 -dioxide, (formula II)

HCTZ has been firstly described in the patent numbered US3025292. In the patent, there are processes to prepare HCTZ. HCTZ is a thiazide derivative diuretic which is used in the treatment of edema and hypertension. Thiazide derivative diuretic increases elimination of sodium, chloro and water by inhibing the passage of sodium from kidney tubulus. The diuretic effect of HCTZ indirectly decreases the plasma volume with the elevations of plasma renin activity, aldosterone secretion and lost of urinary potassium and with the decreases of serum potassium level. The connection of renin- aldosterone comes through angiotensin II. For this reason, the use of diuretics with angiotensin II receptor antagonist is tend to reverse potassium lost caused by diuretics. Antihypertensive mechanism of action of thiazide has not been well understood. Generally, they don't influence blood pressure. Firstly, they lower blood pressure by decreasing cardiac flow rate and plasma and extracellular fluid volume. With the treatment continued a couple of weeks, hypotensive effect continues, despite lower plasma volume has been getting slowly normal. The reason for this is the decrease of peripheral vascular resistance and probably, the decrease of the susceptibility of smooth muscle cells to noradrenaline. The diuresis starts 2 hours after taking orally HCTZ, reach to maximum level approximately in 4 hours and finish in between 6-12 hours.

The synergistic increase of antihypertensive effect of telmisartan and HCTZ is proved with some clinical researches:

• Fenton C, Keating G. M., Scott L. J. Telmisartan/Hydrochlorothiazide: In The Treatment of Essential Hypertension. Drugs 2003; 63 (19): 2013-2026

• Schmieder R. E. Telmisartan/Hydrochlorothiazide Combination Therapy in The Treatment of Essential Hypertension. Expert Opinion on Pharmacotherapy 2004; 5(11) : 2303-

2310

• Lacourciere Y. A New Fixed-dose Combination for Added Blood Pressure Control: Telmisartan + Hydrochlorothiazide. The Journal of International Medical Research,. 2002; 30: 366 - 379

• McGiIl J. B., MD, Reilly P. A., PhD. Telmisartan plus Hydrochlorothiazide versus Telmisartan or Hydrochlorothiazide Monotherapy in Patients with Mild to Moderate Hypertension: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial. Clinical Therapeutics 2001; 23(6)

• Jayaram S., Labott S., Cbandrasekharan S., et al. Assessment of Efficacy, Safety and Tolerability of Fixed Dose Combination of Telmisartan 40mg and Hydrochlorothiazide 12.5mg in Adult Indian Patients with Mild to Moderate Hypertension. Journal of Indian Medical Association 2004; 102(9)

• McGiIl J. B., MD, Reilly P. A., PhD. Combination Treatment with Telmisartan and Hydrochlorothiazide in Black Patients with Mild to Moderate Hypertension. Clinical Cardiology 2001; 24, 66-72 The present invention is intended to achieve an effective combination which provides the desired effect based on the synergistic effect of telmisartan and HCTZ in antihypertensive treatment. To achieve the desired effect, an aspect of the invention is to combine telmisartan and HCTZ in a pharmaceutical form like tablet by providing a formulation in accordance with the invention comprising a pharmaceutically acceptable, non-toxic and therapeutically effective amount of these two agents. When solid dosage forms like tablet are used orally, drug should be dissolved many times in gastrointestinal liquid before showing its effect. However, some drugs having low water solubility can not be absorbed from gastrointestinal system. These drugs having low solubility also influence the bioavailability negatively. Telmisartan is also one of the substances which does not dissolve practically in water or solutions of water having pH between 3 and 9. While it is sparingly soluble in acids except hydrochloric acid, its solubility in strong bases is high. It is stable in basic medium, but it tends to degrade under acidic conditions. Besides, when it is exposed to sunlight, a slight discoloration occurs.

Telmisartan is an active agent exposing polymorphism. The polymorphs of telmisartan are also faced to solubility problems. Polymorph B of telmisartan is described in patent application numbered WO0043370 Al which is characterized with an endothermic pick seen at 183± 2⁰C after DSC analysis .In the application, it is described that polymorph B is turned to polymorph A under temperature and moisture effect. Solubility of said two polymorphs is low.

One of the known techniques applied to address the solubility problem of poorly soluble drugs such as telmisartan is particle size reduction. Because the dissolution rate of a particulate solid depends on the surface area and the surface area increases as the particle size reduces, reducing particle size may increase dissolution rate.

However, particle size reduction may not always effective at increasing the dissolution rate of a drug. Because, many hydrophobic drugs have a strong tendency to agglomerate while being transformed into larger particles during the dosage form manufacturing process depending on an overall decrease in effective surface area. Another technique applied to increase the surface area is nanoparticulate technology. But, there are some barriers faced during the processes for obtaining nanoparticles such as technical and mechanical limitation of breaking the drug particles into the size of nano particles and the stabilization of these small drug particles in the dosage form.

This situation causes search of new methods to overcome solubility problem for drugs like telmisartan having solubility problem.

In the patent numbered EP 1545467 Bl, a pharmaceutical composition is described to solve the solubility problem of free acid form of telmisartan. According to the patent, pharmaceutical composition comprising 3 to 50 wt. % of telmisartan dispersed in a dissolving matrix comprises; a) Basic agent: a basic agent having a telmisartan molar ratio between 1:1— 10:1, b) Surfactant or emulsifϊer in an amount of approximately 1-20% of the finarcomposition, c) Diluent soluble in water in a ratio of 25-70 wt. %

d) Optionally, 0-20 wt. % further excipients.

In the patent application numbered US2007116759 Al, a pharmaceutical composition is described to increase solubility of telmisartan wherein the composition comprises,

a) Telmisartan compound,

b) A surfactant,

c) A basic agent, and

d) At least one diluent selected from water soluble and water insoluble diluents

and wherein the amount of water soluble diluents in the pharmaceutical composition is less than 25% by weight of the pharmaceutical composition.

Pharmaceutical compositions proposed in the above patents and patent applications head to the use of surfactant and emulsifier to remedy the solubility problem. However, it is needed to pharmaceutical compositions produced by an incomplex production method to overcome solubility problem of telmisartan.

In the patent application numbered WO03037876 Al, crystalline telmisartan sodium salt characterized with a melting point of 245 ± 5°C and that preparation process of crystalline telmisartan sodium salt obtained by acid addition salts formed with hydrochloric acid, hydrobromic acid, toluensulphonic acid and methanesulfonic acid; are described. In the patent application numbered WO2006050921 A2, crystalline and amorphous form of alkaline and alkaline earth salts (sodium, potassium, magnesium and calcium) of telmisartan are described. In the patent application numbered WO2007147889 A2, telmisartan salts (ammonium, choline, ters-butyl amine, arginin, meglumin, ethanolamine, piperazine, diethylamine, sulphuric acid, maleic acid, tartaric acid, citric acid, fumaric acid, oxalic acid, benzenesulphonic acid, naphthalene-2-sulphonic acid, tris-(hydroxymethyl)amine) and/or its polymorphs (telmisartan potassium) and its preparation processes are described.

In patents and patent applications defined above, different telmisartan salts and their polymorphs are described in consideration of exhibiting higher solubility than free form. However, any proof is submitted about that these salts really provide a pharmaceutical composition with high solubility and stability, and a formulation is not proposed for most of them.

By contrast with telmisartan, HCTZ is a substance which is easily soluble in aqueous solutions. However, it is incompatible with basic agents. For this reason, in case of the combination of telmisartan and HCTZ, as well as solubility problem of telmisartan, incompatibility problem with substances of composition also arises. Because, when basic agents increasing solubility and stability of telmisartan contact with HCTZ, they cause incompatibility. Depending to the incompatibility, stability problem arises in tablets.

Another method described in the patent numbered EP 1467712 Bl, is to produce separate film coated tablet in the size and shape which can be filled in capsule for telmisartan and HCTZ. However, division of doses to form small tablets causes the decrease of dissolution rate.

The patent numbered EP 1467712 Bl, bilayer pharmaceutical tablet formulation comprising telmisartan and HCTZ and its production method are described. However, because of that bilayer tablet production should be prepared by taking into consideration of stability caused by release properties, solubility and incompatibility, it is a complicated application.

According to these informations, many alternatives are tried to overcome the solubility problem of telmisartan, the incompatibility between substances forming composition comprising telmisartan and HCTZ and thereby the stability problem. However, present invention presents a novel composition and an incomplex production method to provide targeted therapeutic efficiency of telmisartan which have solubility problem and which can be stable in only basic medium and targeted therapeutic activity of HCTZ which is incompatible with basic agents needed to formulate telmisartan. With the difference of formulations of said patents and patent applications, pharmaceutical composition of this invention proposes to the solubility problem of telmisartan without the need of using surfactant and emulsifier. The incompatibility problem between HCTZ and basic substances which are necessary to formulate telmisartan is solved with an incomplex production method wherein active ingredients are formulated separately. The characteristic of the invention is adding ammonium during the preparation of formulation to increase telmisartan' s solubility and to ensure its stability and spontaneous generation of telmisartan ammonium salt which has a solubility higher than free acid without the need of another process as different from above patent and patent applications described in the prior art. Another embodimentof the invention is formulating active ingredients separately to overcome incompatibility and thereby stability problem and adding tromethamine as stabilizing agent to the formulation. Obtained composition is a composition having improved solubility and stability properties and is effective in the treatment of hypertension. Summary of the Invention

The present invention relates to a process for preparation of pharmaceutical composition comprising a therapeutically effective amount of telmisartan and a therapeutically effective amount of HCTZ for use in the manufacture of a medicament for the treatment of essential hypertension, characterized in that telmisartan and HCTZ are preformulated in a series of manufacturing process steps and that ammonia is used during the preparation of composition.

According to the present invention, the manufacturing process which provides a formulation so as to obtain the desirable effect is as follows: a granulation solution is obtained by adding and dissolving telmisartan, tromethamine and optionally at least one pharmaceutically acceptable excipient, preferably a binder in the solution of ammonia mixed with a suitable pure solvent or solvent mixture, preferably water; granulation is made by spraying granulation solution on a pharmaceutically acceptable diluent;

first mixture is obtained by drying obtained granules at 50°C to have maximum 2% of moisture and sieving; secondary mixture is obtained by mixing and sieving HCTZ with at least one pharmaceutically acceptable excipient selected from at least one diluent, dispenser and glidant; both mixtures are mixed to obtain a homogeneous tablet; final mixture is optionally treated with at least one pharmaceutically acceptable excipient, preferably a lubricant and is made to ready for the pressing;

optionally, tablets are coated.

Detailed Description of the Invention

The present invention is directed to obtain a combination of HCTZ and telmisartan which provides the desired effect, depending on the synergically increasing antihypertensive effect of HCTZ and angiotensin II receptor antagonists. However, there are solubility problem of telmisartan and incompatibility, also stability problem between substances forming the composition comprising HCTZ and telmisartan are faced during the studies as defined above, the An in-complex method should be generated to overcome the solubility problem of telmisartan and the incompatibility problem between substances forming the composition and on the other hand, therapeutically effective amount of active agents and suitable amount of excipients should be found to provide the desired effect of the combination of telmisartan and HCTZ.

As a result of studies, it is surprisingly found that pharmaceutical composition comprising telmisartan and HCTZ preformulated in a series of manufacturing process steps and the use of ammonia during its preparation provides optimum activity for the treatment of essential hypertension.

Another embodiment of the invention, it is found that composition comprising telmisartan and HCTZ in certain ratios, a sufficient amount of ammonia, andtromethamine and optionally at least one pharmaceutically acceptable excipient selected from substances as diluent, binder, disintegrant, lubricant and glidant provides optimum efficiency for the treatment of essential hypertension.

The solubility problem of telmisartan is solved with a composition wherein the content of the composition is established according to the solubility properties of the substance and with an incomplex production method. The incompatibility problem between HCTZ and basic substances which are necessary to formulate telmisartan is solved with an incomplex production method wherein active ingredients are formulated separately. The pharmaceutical composition comprises telmisartan as active ingredient is in the form of free acid. However, when telmisartan contacts with ammonia which is added to composition for increasing solubility and ensuring stability, telmisartan ammonium salt is obtained spontaneously. Therefore, there is no need for further process to obtain telmisartan ammonium salt. Tromethamine adding to the pharmaceutical composition is also increasing the stability of composition.

During the preparation of first mixture, a granulation solution is obtained by adding telmisartan, tromethamine as a stabilizing agent and optionally at least one pharmaceutically acceptable excipient, preferably a binder, in the solution of ammonia mixed with a suitable pure solvent or solvent mixture, preferably water. Then, granulation is made by spraying this granulation solution on a pharmaceutically acceptable diluent. Obtained granules are dried at 50°C to have maximum 2% of moisture and sieved. Granules obtained with this method exhibit 80% solubility in the dissolution medium in first 20 minutes.

- During the preparation of secondary mixture, HCTZ is mixed and sieved with at least one pharmaceutically acceptable excipient selected from at least one diluent, disintegrant and glidant.

The final mixture which is generated by combining obtained mixtures is made ready for tablet press by treating optionally at least one pharmaceutically acceptable excipient, preferably a lubricant.

- Tablets are optionally coated with film coating.

The terms of "Certain ratio", "sufficient amount" and "optionally" mean telmisartan in the range of 0.1-40% by weight, HCTZ in the range of 0.1-20% by weight, ammonia in the range till 10% by weight, tromethamine in the range of 0.1-20% by weight and usage of at least one pharmaceutically acceptable excipient selected from additives as diluent, binder, dispenser, lubricant and glidant when needed; which are preferred to obtain the desired therapeutic activity.

Pharmaceutically acceptable diluents can be selected from lactose, microcrystalline, cellulose, starch, pre-gelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, caoline, lactilol, powder cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol. In the first mixture of telmisartan, sorbitol or mannitol are preferably used; in the secondary mixture of HCTZ, lactose and/or microcrystalline cellulose are preferably used. In pharmaceutical formulation, diluent is present preferably in the range of 0-95% by weight and more preferably 5-85% by weight. Pharmaceutically acceptable binders are selected from starches (as potatoes starch, corn starch, wheat starch), sugars as sucrose, glucose, dextrose, lactose, maltodextrine, natural and synthetic gums (as acacia), gelatin, cellulose derivative (as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellylose), polyvinylpyrrolidone, polyethylene, glycol, wax, calcium carbonate, calcium phosphate, alcohols (as sorbitol, xilitol, mannitol) and water. Preferably, polyvinylpyrrolidone (povidone) is used. In the pharmaceutical formulation, binder is present preferably in the range of 0-10% by weight, more preferably 0.1-5% by weight. Pharmaceutically acceptable disintegrants are selected from starch (corn starch, potatoes starch) sodium starch glycolate, pre-gelatinized starch, cellulose derivative (as croscarmellose sodium or microcrystalline cellulose), polyvinylpyrrolidone, crospovidone, alginic acid, sodium alginate, clays (as xanthane gum or veegum), ion-exchange resins, food acids and effervescent systems based on alkali carbonate compounds. Preferably, a starch derivative is used. In pharmaceutical formulation, disintegrantr is present preferably in the range of 0-10% by weight, more preferably 0.1-5% by weight.

Pharmaceutically acceptable lubricants are selected from metallic stearate (as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (as sodium stearyl fumarate), fatty acids (as stearic acids), fatty alcohols, glyceryl behenate, mineral oil, paraffines, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates (as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc. Preferably, magnesium stearate is used. In pharmaceutical formulation, lubricant is present preferably in the range of 0-10% by weight, more preferably 0.1-5% by weight.

Pharmaceutically acceptable glidants are selected from silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, calcium phosphate tribasic, stearates metallic, metallic lauryl sulfates and calcium silicate. Preferably, silicon dioxide is used. In pharmaceutical formulation, glidant is present in the range of less than 1% by weight.

In addition; other pharmaceutically acceptable excipients such as resolution modulators, electrolytes, sweeteners, coloring agents and coatings can be used in the formulation. The examples of pharmaceutical formulation according to the invention are given below. These examples are given to explain the scope of invention and the subject is not limited with these examples.

Examples

Example 1.

Claims

1. A process for the preparation of pharmaceutical composition comprising a therapeutically effective amount of telmisartan and a therapeutically effective amount of HCTZ for use in the manufacture of a medicament for the treatment of essential hypertension, characterized in that telmisartan and HCTZ are preformulated in a series of manufacturing process steps and that ammonia is used during the preparation of composition.

2. The process according to claim 1, characterized in that a granulation solution is obtained by adding and dissolving telmisartan, tromethamine and optionally at least one pharmaceutically acceptable excipient, preferably a binder, in the solution of ammonia mixed with a suitable pure solvent or solvent mixture, preferably water; granulation is made by spraying granulation solution on a pharmaceutically acceptable diluent and first mixture is obtained by drying and sieving obtained granules.

3. The process according to claim 1, characterized in that secondary mixture is obtained by mixing and sieving HCTZ with at least one pharmaceutically acceptable excipient selected from at least one diluent, disintegrant and glidant.

4. The process according to claim 1, characterized in that both mixtures are mixed to obtain homogenous tablet and, final mixture optionally is treated with at least one pharmaceutically acceptable excipient, preferably a lubricant and is made to ready for the tablet pressing.

5. The pharmaceutical composition prepared by the method according to claims 1 to 4, characterized in that with respect to the total weight of the tablet core, pharmaceutical composition comprises,

- Telmisartan in the range of 0.1 -40% by weight,

HCTZ in the range of 0.1 -20% by weight,

ammonia in the range till 10% by weight,

at least one pharmaceutically acceptable excipient selected from stabilizing agent, diluent, binder, dispenser, lubricant and glidant.

6. The pharmaceutical composition prepared by the method according to claims 1 to 4, characterized in that with respect to the total weight of the tablet core, pharmaceutical composition comprises,

Telmisartan in the range of 0.1 -40% by weight,

- HCTZ in the range of 0.1 -20% by weight,

ammonia in the range till 10% by weight,

tromethamine in the range of 0.1 -20% by weight,

at least one pharmaceutically acceptable excipient selected from stabilizing agent, diluent, binder, disintegrant, lubricant and glidant.

7. The pharmaceutical composition prepared by the method according to claims 1 to 4, characterized in that pharmaceutical composition comprises preferably sorbitol or mannitol in the first mixture of telmisartan and preferably lactose and/or microcrystalline cellulose in the secondary mixture of HCTZ.

8. The pharmaceuticalcomposition according to claim 7, characterized in that diluent is present preferably in the range of 0-95% by weight and more preferably 5-85% by weight.

9. The pharmaceutical composition prepared by the method according to claims 1 to 4, characterized in that pharmaceutical composition comprises preferably polyvinylpyrrolidone as binder.

10. The pharmaceutical composition according to claim 9, characterized in that binder is present preferably in the range of 0-10% by weight and more preferably 0.1-5% by weight.

11. The pharmaceutical composition prepared by the process according to claims 1 to 4, characterized in that pharmaceutical composition comprises preferably a starch derivative as disintegrant.

12. The pharmaceutical composition according to claim 11, characterized in that disintegrant is present preferably in the range of 0-10% by weight and more preferably 0.1-5% by weight.

13. The pharmaceutical composition prepared by the process according to claims 1 to 4, characterized in that pharmaceutical composition comprises preferably magnesium stearate as lubricant.

14. The pharmaceutical composition according to claim 13, characterized in that lubricant is present preferably in the range of 0-10% by weight and more preferably 0.1-5% by weight.

15. The pharmaceutical composition prepared by the process according to claims 1 to 4, characterized in that pharmaceutical composition comprises preferably silicon dioxide as glidant.

16. The pharmaceutical composition according to claim 15, characterized in that glidant is present preferably in the range of less than 1% by weight.

17. The pharmaceutical composition according to preceding claims, characterized in that pharmaceutical composition is in solid dosage form for oral use.

18. The pharmaceutical composition according to claim 17, characterized in that solid dosage form is in the form of tablet, preferably film tablet.