WO2011002423A2

WO2011002423A2 - Solubility enhancing pharmaceutical composition

Info

Publication number: WO2011002423A2
Application number: PCT/TR2010/000124
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2009-07-02
Filing date: 2010-06-25
Publication date: 2011-01-06
Also published as: EP2448576A2; WO2011002423A3

Abstract

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

Description

SOLUBILITY ENHANCING PHARMACEUTICAL COMPOSITION

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.

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 disease 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]-l'- 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 mentioned.

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.

The present invention is directed to obtain an effective composition which provides the desired effect based on the strong antihypertensive effect of telmisartan.

To achieve the desired effect, an aspect of the invention is to provide a formulation in accordance with the invention comprising a pharmaceutically acceptable, non-toxic and therapeutically effective amount of telmisartan and to formulate this agent in the form of tablet.

When solid dosage forms like tablet are used orally, mostly drug should be dissolved 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 in a negative way. Telmisartan is also one of the substances which practically does not dissolve in water or in aqueous solutions 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 displaying polymorphism. The polymorphs of telmisartan are also faced with 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 be 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 emulsifier in an amount of approximately 1-20% of the final composition,

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,

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, there is need for pharmaceutical compositions produced by an incomplex production method to overcome solubility problem of telmisartan.

There are some other patent applications of salts of telmisartan and/or its polymorphs which are prepared by depending on the fact that the acidic and basic salts of telmisartan display a higher solubility profile than free form as listed below.

In the patent application numbered WO03037876 Al, crystalline telmisartan sodium salt characterized with a melting point of 245 ± 5⁰C 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, no proof is submitted whether these salts really provide a pharmaceutical composition with high solubility and stability or not, and a formulation is not proposed for most of them.

According to these informations, many alternatives are tried to overcome the solubility problem of telmisartan. 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.

Unlike the formulations in patents and patent applications given above, pharmaceutical composition of this invention proposes to address the solubility problem of telmisartan without the need of using surfactant and emulsifier. 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 using another additional process. Pharmaceutical formulations according to the present invention include trometamine as stabilizing agent in order to increase stability 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 for use in the manufacture of a medicament for the treatment of essential hypertension, characterized in 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 granμlation 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 diluents preferably on mannitol or sorbitol;

- The final mixture is obtained by addition of at least one pharmaceutically acceptable excipient, preferably a lubricant after drying granules obtained in previous steps at 50°C to have maximum 2% of moisture and sieving the final mixture is then mixed to obtain a homogeneous mixture and fed to the tablet press machine

Optionally the tablets are coated.

Detailed Description of the Invention

The present invention is directed to obtain a composition which provides the desired effect depending on antihypertensive effect of telmisartan. However a solubility problem was arised during the studies conducted for this purpose as mentioned before. 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 telmisartan composition.

As a result of studies, it is surprisingly found that pharmaceutical composition comprising telmisartan wherein ammonia is used during the preparation provides optimum activity for the treatment of essential hypertension.

As another embodiment of the invention, it is found that a composition comprising telmisartan in certain ratios, a sufficient amount of ammonia, and tromethamine and optionally at least one pharmaceutically acceptable excipient selected from a group of substances comprising 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 pharmaceutical composition comprises telmisartan as active ingredient 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. In this way 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 diluents, preferably on mannitol or sorbitol.

- Afterwards, the final mixture is obtained by addition of at least one pharmaceutically acceptable excipient, preferably a lubricant after drying granules obtained in previous steps at 50°C to have maximum 2% of moisture and sieving.

And finally, the final mixture is fed into the tablet press machine after mixing homogeneously.

Tablets are optionally coated with a film coating.

Tablets obtained with this method exhibit 80% solubility in the dissolution medium in first 20 minutes.

The terms of "certain ratio", "sufficient amount" and "optionally" mean telmisartan in an amount in the range of 0.1-40% by weight, ammonia in an amount in the range up to 10% by weight, tromethamine in an amount in the range of 0.1-20% by weight and use 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 a group comprising 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, powdered cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol. Preferably sorbitol or mannitol is used. Diluent is present in an amount preferably in the range of 0-95% by weight and more preferably 5-85% by weight.

Pharmaceutically acceptable binders are selected from starches (as potato 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, potato 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. In pharmaceutical formulation, disintegrant 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 stearates (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, metallic stearates, metallic lauryl sulfates and calcium silicate. 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.

Example 2.

Example 3.

Claims

1. A process for the preparation of pharmaceutical composition comprising a therapeutically effective amount of telmisartan for use in the manufacture of a medicament for the treatment of essential hypertension, characterized in 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; the granulation is then carried out by spraying the granulation solution onto a pharmaceutically acceptable diluent, preferably on maltitol or sorbitol; The obtained granules are then dried and sieved and optionally mixed with other excipients, optionally a lubricant to give the final mixture and the final mixture is then mixed homogeneously and fed into a tablet pressing machine.

3. The pharmaceutical composition prepared by the method according to claims 1 to 2, characterized in that with respect to the total weight of the tablet core, pharmaceutical composition comprises

- Telmisartan in an amount in the range of 0.1 -40% by weight

Ammonia in an amount in the range of up to 10% by weight and

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

4. The pharmaceutical composition prepared by the method according to claims 1 to 2, characterized in that with respect to the total weight of the tablet core, pharmaceutical composition comprises

- Telmisartan in an amount in the range of 0.1 -40% by weight

- Ammonia in an amount in the range of up to 10% by weight

- Tromethamine in an amount in the range of 0.1 -20% by weight, and

- Optionally, at least one excipient selected from a group comprising diluent binder, disintegrant, lubricant and glidant.

5. The pharmaceutical composition prepared by the method according to claims 1 o^'r 2 charcterized in that said composition comprises sorbitol or mannitol as diluent.

6. The pharmaceutical composition according to claim 5, characterized in that diluent is present in an amount preferably in the range of 0-95 %, more preferably in the range of 5-85 %.

7. The pharmaceutical composition prepared by the method according to claims 1 or 2 characterized in that said pharmaceutical composition preferably comprises polyvinylpyrrolidone as binder.

8. The pharmaceutical composition according to claim 7, characterized in that binder is preferably present in an amount in the range of 0-10% by weight and more preferably 0.1-5% by weight.

9. The pharmaceutical composition prepared by the method according to claims 1 or 2 characterized in that said pharmaceutical composition preferably comprises magnesium stearate as lubricant.

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

11. The pharmaceutical composition according to any of the preceding claims, characterized in that pharmaceutical composition is in solid dosage form for oral use.

12. The pharmaceutical composition according to claim 11, characterized in that solid dosage form is in the form of tablet, preferably film tablet.