ZA200507223B

ZA200507223B - Pharmaceutical formulation of the sodium salt of telmisartan

Info

Publication number: ZA200507223B
Application number: ZA200507223A
Authority: ZA
Inventors: Anja Kohlrausch
Original assignee: Boehringer Ingelheim Int
Priority date: 2003-04-30
Filing date: 2005-09-08
Publication date: 2006-05-31
Also published as: RU2005137031A; DE10319450A1; CA2524091A1; EP1622612B1; ATE388703T1; TWI364278B; RU2372918C2; CN1780618A; DE502004006500D1; CN100589802C; NZ543775A; DK1622612T3; CA2524091C; AU2004233581B2; EP1622612B9; UY28293A1; BRPI0409809A; IL171465A; JP2006524635A; EP1622612A1

Description

01-1491 Boehringer Ingelheim Pharma GmbH & Co. KG

D-55216 Ingelheim/Rhein 83675

Pharmaceutical formulation of the telmisartan sodium salt

The invention relates to a pharmaceutical formulation of the crystalline sodium salt of 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1- yimethyl]biphenyl-2-carboxylic acid (telmisartan), as well as processes for the preparation thereof.

Background to the invention

The compound telmisartan is known from European Patent EP 502 314 B1 and has the following chemical structure:

Me

N Me

CX —

N N as j=vy ®

Telmisartan, and the physiologically acceptable salts thereof, have valuable pharmacological properties. Telmisartan is an angiotensin antagonist, particularly an angiotensin-Il-antagonist which by virtue of its pharmacological properties may be used for example to treat hypertension and cardiac insufficiency, to treat ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), to prevent the progression of cardiac insufficiency after myocardial infarct, to treat diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases. Other possible therapeutic applications can be found in EP 502314 B1 and WO 02/15891, the contents of which are hereby referred to.

Hydrochlorothiazide (HCTZ) is a thiazide diuretic which is taken orally to treat oedema and high blood pressure. The chemical name of HCTZ is 6-chloro- 3,4-dihydro-2H-1,2,4-benzothiadiazin-7-sulphonamide-1,1-dioxide and the compound is described by the following structural formula:

I o Cl

H o “0 SO,-NH,

Telmisartan is commercially obtainable under the brand name Micardis®, while a combination of telmisartan with hydrochlorothiazide (HCTZ) is commercially obtainable under the brand name Micardis Plus®. Starting from the free acid of telmisartan, these formulations are produced by a complex spray drying process. Because of the limited solubility of the free acid, less complex methods of preparing an alternative preparation are difficult to achieve.

The aim of the present invention is to provide telmisartan in a form which enables a formulation of this active substance to be prepared in a less complex form. It has to be borne in mind that generally the production of a composition containing a pharmaceutically active substance is dependent on various parameters which are linked to the nature of the active ingredient itself. Without being tied thereto, examples of these parameters are the stability of effect of the starting material under different environmental conditions, the stability during the manufacture of the pharmaceutical formulation and the stability in the final compositions of the pharmaceutical preparation. The pharmaceutically active substance used to prepare the above mentioned pharmaceutical composition should be as pure as possible.

At the same time its stability on long-term storage must be guaranteed under various environmental conditions. This is absolutely essential, in order to prevent pharmaceutical compositions being used which contain, in addition to the active substance proper, breakdown products thereof. In such a case the content of active substance present in a preparation produced therefrom may be less than the specified amount.

Another aspect which is important in the production of solid preparations is that the active substance should have the most stable possible crystalline morphology for the pharmaceutical quality of a medicinal formulation. If this is not the case, the morphology of the active substance may change in certain circumstances under the conditions of manufacture of the preparation. Such a change may in turn affect the reproducibility of the manufacturing process and thus lead to final formulations which do not meet the high quality requirements imposed on pharmaceutical formulations. To this extent it should generally be borne in mind that any change to the solid state of a pharmaceutical composition which can improve its physical and chemical stability gives a significant advantage over less stable forms of the same drug.

The object of the invention is thus to provide a new pharmaceutical composition containing a stable form of telmisartan which complies with the above mentioned stringent requirements imposed on a pharmaceutically active substance.

Detailed description of the invention

Surprisingly, it has been found that telmisartan can be obtained in crystalline form, in the form of its sodium salt of formula 1

Me " Sess

N N

(J 1

By a suitable choice of manufacturing conditions, the polymorphic form of the crystalline sodium salt which meets the requirements mentioned above can be obtained selectively.

This crystalline form of the sodium salt of telmisartan is characterised by a melting point of T=245 + 5°C (determined by DSC=Differential Scanning

Calorimetry; heating rate: 10 K/min).

The following Table 1 summarises the data obtained in a spectroscopic analysis of the salt:

Table 1: [%] [%] “seo | swe | 8 eat | sas | 8 702 | tear | 2 || oe | si | 10 ras | sor | os “ie10 | 4% | 9 “eao | 1041 | 6 ~ oe | se | 8 “e219 | 400 | 9 “e376 | ara | 9 204s | ses | 8

In the above Table the value "2 © [°]" denotes the angle of diffraction in degrees and the value "d [A]" denotes the lattice plane spacings determined in A.

According to the findings given in Table 1, the crystalline telmisartan sodium salt is characterised in that in the X-ray powder diagram it has the characteristic values d= 20.95 A, 17.72 A, 13.97 A and 13.63 A, inter alia.

The X-ray powder diagrams were recorded within the scope of the present invention using a Bruker D8 Advanced with an SSD (= site-sensitive detector) (CuK, - radiation, = 1.5418 A, 30 kV, 40 mA).

The crystalline sodium salt of telmisartan according to the invention may also be present in the form of the solvates and hydrates thereof, preferably in the form of the hydrates, most preferably in the form of the hemihydrate thereof.

In another aspect, the present invention relates to a method of producing the crystalline sodium salt of telmisartan according to the invention. The starting material used to prepare the crystalline sodium salt of telmisartan according to the invention may be the free acid of telmisartan, which may be obtained by methods known in the art (e.g. according to EP 502314 A1).

To prepare the crystalline sodium salt according to the invention the free acid of telmisartan is taken up in a suitable solvent, preferably in an organic aprotic solvent, most preferably in an organic, aprotic and non-polar solvent. The solvents used according to the invention are most preferably toluene, chloroform, dichloromethane, tetrahydrofuran, diethylether, diisopropylether, methyl-tert. butylether, acetone, methylisobutylketone, benzene or acetonitrile, of which toluene, benzene and methylisobutylketone are particularly preferred. Of outstanding importance according to the invention is toluene as solvent.

As a rule, between 0.5 and 5 ml, preferably between 1 and 3 ml, most preferably between 1.5 and 2.5 ml of the above mentioned solvent are used per gram of the free acid of telmisartan.

A suitable sodium salt is then added as a base to this solution or suspension.

Suitable sodium salts within the scope of the present invention include sodium hydroxide, sodium hydride, sodium carbonate, sodium hydrogen carbonate or sodium alkoxides. By sodium alkoxides are meant the sodium salts which are formed with lower alcohols, preferably with alcohols selected from among methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec.-butanol, isobutanol, n-butanol and tert.-amylalcohol. Of particular interest according to the invention are sodium salts selected from among sodium hydroxide, sodium hydride, sodium ethoxide and sodium methoxide; of these, sodium hydroxide and sodium methoxide are of particular importance according to the invention. The above mentioned sodium salts may be added to the reaction mixture as solids. However, in the case of sodium hydroxide this is preferably added in the form of aqueous solutions. It is particularly preferable to use concentrated aqueous solutions of sodium hydroxide. For example, sodium hydroxide solution may be used in a concentration of about 45 wt.-%.

The amount of sodium salt to be used naturally depends on the amount of free acid telmisartan used. According to the invention at least 1 mol of sodium salt has to be added per mol of telmisartan. It is also possible according to the invention to add an excess of sodium salt. Preferably, 1-2.5, more preferably 1-2, most preferably 1-1.5 mol of sodium salt are added per mol of the acid telmisartan used.

If sodium hydroxide is used as the sodium salt and this is added in the form of an aqueous solution, according to a preferred embodiment of the process according to the invention, it may be helpful in some cases to add a water- miscible organic solvent. This is preferably selected from among methanol, ethanol, isopropanol, acetone, tetrahydrofuran, tert.-butanol, 2-butanol, butanol, glycol, ethyldiglycol, 1,3-butanediol, 1,4-butanediol, tert.-amylalcohol, acetonitrile, nitromethane, formamide, dimethylformamide, N- methylpyrrolidinone, dimethylsulphoxide, dimethylacetamide, nitroethane and methoxy-2-propanol, of which the above mentioned alcohols are particularly significant. It is particularly preferred, within the scope of the process according to the invention, to use methanol or ethanol, above all ethanol.

Preferably, between 50 and 500 ml, more preferably between 100 and 400 ml, most preferably between 200 and 350 mi of this solvent are used per mol of telmisartan used, according to the invention.

Then the reaction mixture may be heated to speed up the progress of the reaction. Preferably, the reaction mixture is heated to a temperature of >40°C, most preferably to over 60°C, with thorough mixing. The maximum temperature which may be selected is naturally determined by the boiling temperature of the solvents used. If the solvents preferred according to the invention are used, the mixture is preferably heated to over 70°C. This heating is generally carried out for a period of from 15 minutes to 2 hours, preferably between 20 minutes and one hour. Then the solution obtained is filtered and any solid remaining in the filter is washed with one or more of the above mentioned solvents.

The filtrate obtained by the process described above is added slowly, preferably dropwise, to an organic solvent which is heated to a temperature of >40°C, preferably above 60°C, most preferably to boiling point. The solvent used is preferably an organic aprotic solvent, more preferably an organic, aprotic and non-polar solvent. Solvents which may be used according to the invention are, most preferably, toluene, chloroform, dichloromethane, tetrahydrofuran, diethylether, diisopropylether, methyl-tert. butylether, acetone, methylisobutylketone, benzene or acetonitrile, of which toluene, benzene and methylisobutylketone are particularly preferred. The solvent toluene is of exceptional importance according to the invention. At the same time as the filtrate is added to the heated solvent, in a preferred embodiment of the invention, some of the solvent is distilled off (optionally azeotropically).

After all the filtrate has been added, more solvent (e.g. about one to two thirds of the total amount of solvent added by this stage) may optionally be removed by distillation.

The concentrated solution thus obtained is cooled, preferably to ambient temperature, whereupon the telmisartan sodium salt crystallises out. After crystallisation is complete the crystals are separated off, optionally washed with the organic solvent mentioned above and finally dried.

The crystalline telmisartan sodium salt according to the invention may also be obtained starting from the acid addition salts of formula 2

Me

N Me 1 LX —

N oo (0 2 wherein H-X denotes an acid selected from among hydrochloric acid, hydrobromic acid, toluenesulphonic acid or methanesulphonic acid. Of the above mentioned acid addition salts of formula 2 the salt wherein H-X denotes hydrochloric acid is of particular significance. This acid addition salt is also referred to hereinafter as telmisartan hydrochloride.

The compounds of formula 2 may be obtained for example from tert.-butyl 4°- [2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl}- methyl]-biphenyl-2-carboxylate (=tert.-butyl ester of telmisartan) known from the prior art by saponification in acetic acid in the presence of the acid H-X.

In order to prepare the crystalline telmisartan sodium salt of formula 1 according to the invention starting from the acid addition salts of formula 2 the following procedure may be used, according to the invention.

The compound of formula 2 is taken up in a suitable solvent and combined with a suitable sodium salt.

The solvent may be water and/or a suitable alcohol, such as methanol, ethanol or isopropanol mixed with an aprotic organic solvent selected from among toluene, chloroform, dichloromethane, tetrahydrofuran, diethylether, diisopropylether, methyi-tert. butylether, acetone, methylisobutylketone, benzene and acetonitrile. It is particularly preferred to use, as the solvent, water mixed with ethanol or isopropanol mixed with an aprotic organic solvent selected from among toluene, benzene and methylisobutylketone, most preferably toluene. A mixture of water, isopropanol and toluene has proved particularly suitable for this step of the synthesis.

The amount of solvent or solvent mixture used depends on the amount of acid addition salt 2 used. Preferably, about 0.3 — 3.5 L, preferably about 1 —2.51L, more preferably about 1.5 - 2 L of the above mentioned solvent or solvent mixture are used per mol of compound 2 used. If the solvent used is the preferred solvent mixture according to the invention which contains an alcohol as the third solvent component in addition to water and an aprotic organic solvent, the ratios by volume of water to aprotic organic solvent according to the invention are preferably in a range from 1:5 to 1:50 and the ratio of water to alcohol used is in a range from 2:1 to 1:40. Preferably, in a solvent mixture of this kind, the ratios of water to aprotic organic solvent are in the range from 1:10 to 1:30, preferably in the range from 1:15 to 1:25 and the ratio of water to alcohol used is in a range from 1:1 to 1:20, preferably in the range from 1:5 to 1:15.

Preferably, the solvent or solvent mixture mentioned above contains about 10 to 100 mi of water, preferably about 30 to 80 ml of water, most preferably about 40 to 70 ml of water, per mol of 2. Preferably the solvent or solvent mixture used also contains about 100 to 1000 ml of alcohol, preferably about 300 to 800 ml! alcohol, most preferably about 400 to 700 ml alcohol, per mol of 2. Finally, the solvent or solvent mixture used preferably contains as the third component of the solvent, about 200 to 2000 ml of the above mentioned aprotic organic solvent, preferably about 600 to 1600 mi, most preferably about 800 to 1400 ml of the above mentioned aprotic organic solvent, per mol of 2.

Suitable sodium salts which may be used for reacting 2 to 1 include sodium hydroxide, sodium hydride, sodium carbonate, sodium hydrogen carbonate or sodium alkoxides. By sodium alkoxides are meant the sodium salts which are formed with lower alcohols, preferably with alcohols selected from among methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec.-butanol, isobutanol, n-butanol and tert.-amylalcohol. Of particular interest according to the invention are sodium salts selected from among sodium hydroxide, sodium hydride, sodium ethoxide and sodium methoxide, while the sodium alkoxides sodium ethoxide and sodium methoxide, particularly sodium methoxide are of particular importance according to the invention for this reaction step. The above mentioned sodium salts may be added to the reaction mixture as solids. In the case of sodium methoxide however it is preferable to add it in the form of a methanolic solution. Methanolic solutions of sodium methoxide which contain it in a concentration of at least 10%, most preferably about 20-40 % (w/w) , are particularly preferred. For example, the methanolic sodium methoxide solution used may have a concentration of about 30 wt.%.

The amount of sodium salt to be used is naturally dependent on the amount of free acid telmisartan used. According to the invention, at least 2 mol of sodium salt have to be added per mol of telmisartan acid addition salt of formula 2 used. According to the invention it is also possible to add an excess of sodium salt.

It may be useful in some cases to add activated charcoal to the above mentioned reaction mixture. For example, it may be added in an amount of about 5 - 50 g per mol of 2 used, preferably in an amount of about 10-40 g per mol of 2 used.

After the sodium salt and optionally the activated charcoal has been added the reaction mixture obtained is heated to a temperature of about 50-100°C, preferably about 60-90°C, most preferably about 70-80°C for a period of about minutes to 2 hours, preferably for about 20-45 minutes. In the course of this heating, some of the solvent, preferably about 10-50%, most preferably about 20-40% of the total quantity of solvent may be distilled off.

The remaining suspension is then filtered, the filter residue is optionally washed with one of the above mentioned aprotic organic solvents, preferably with the aprotic organic solvent which is also used in the reaction.

The filtrate obtained is then diluted with a solvent or mixture of solvents. Itis preferable to use a mixture of water and the above mentioned aprotic organic solvent for this. Preferably, at this point, about 10 to 100 ml of water, preferably about 30 to 80 ml of water, most preferably about 40 to 70 mi of water are used per mol of the compound 2 originally used. At this point, 250 to 3000 ml, preferably about 800 to 2000 ml, most preferably about 1200 to 1800 ml of aprotic organic solvent are used per mole of the compound 2 originally used.

After dilution, the mixture obtained is refluxed. Then about 1-2 L, preferably about 1200 to 1800 ml of solvent are distilled off per mole of the compound 2 originally used. After the solvent has been distilled off the telmisartan-sodium salt 1 according to the invention crystallises out. The crystals obtained are isolated, optionally washed with one of the above mentioned aprotic organic solvents and finally dried.

Crystalline telmisartan-sodium salt may also be obtained by the methods described above in the form of the solvates or hydrates thereof, preferably in the form of the hydrates thereof, most preferably in the form of the hemihydrate.

In view of the pharmaceutical activity of the crystalline telmisartan sodium salt according to the invention, it is used for preparing a pharmaceutical composition, particularly for preparing a pharmaceutical composition for the prevention or treatment of diseases wherein the administration of therapeutically effective doses of one or more angiotensin-ll-antagonists may provide a therapeutic benefit. Preferably, the present invention relates to the use of crystalline telmisartan-sodium salt for preparing a pharmaceutical composition for the prevention or treatment of diseases selected from among hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), myocardial infarct, the progression of cardiac insufficiency after myocardial infarct, the prevention of cardiovascular deaths, stroke, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, glaucoma, gastrointestinal diseases and bladder diseases, the prevention or treatment of hypertension, cardiac insufficiency, myocardial infarct and stroke and the prevention of cardiovascular deaths being particularly preferred.

Accordingly, the present invention is directed to a pharmaceutical composition characterised in that it contains telmisartan-sodium salt optionally combined with other active substances such as diuretics.

For this purpose the active substance or substances are generally formulated with one or more excipients such as mannitol, sorbitol, xylitol, saccharose, calcium carbonate, calcium phosphate, lactose, croscarmellose sodium salt (cellulose carboxymethylether sodium salt, cross-linked), crospovidone, sodium starch glycolate, hydroxypropylcellulose (low-substituted), maize starch, polyvinylpyrrolidone, copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose or starch, magnesium stearate, sodium stearylfumarate, talc, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, carboxymethyiceliulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

In a pharmaceutical composition containing the telmisartan sodium salt as the sole active substance, one or more excipients such as sorbitol, xylitol, saccharose, croscarmellose sodium salt, crospovidone, sodium starch glycolate, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose or sodium stearylfumarate, hydroxypropylmethylcellulose, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearylalcohol, carboxymethyicellulose or fatty substances such as hard fat or suitable mixtures thereof may be used, in particular. Corresponding tablets may be obtained for example by mixing the active substance or substances with one or more excipients and subsequently compressing them. Examples of excipients are

Claims

Patent Claims

1. Pharmaceutical composition containing the telmisartan sodium salt and a diuretic.

2. The composition according to claim 1 containing one or more formulation excipients selected from among mannitol, sorbitol, xylitol, saccharose, calcium carbonate, calcium phosphate, lactose, croscarmellose sodium salt, crospovidone, sodium starch glycolate, hydroxypropylcellulose, maize starch, polyvinylpyrrolidone, copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), hydroxypropylcellulose, hydroxypropylmethylceliulose, microcrystalline cellulose or starch, magnesium stearate, sodium stearylfumarate, talc, hydroxypropylmethylceliulose, carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof.

3. Pharmaceutical composition containing the telmisartan sodium salt, optionally a diuretic, and one or more formulation excipients selected from among sorbitol, xylitol, saccharose, croscarmellose sodium salit, crospovidone, sodium starch glycolate, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose or sodium stearylfumarate, hydroxypropylmethylcellulose, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearylalcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof.

4. The composition according to claims 1 to 3 containing the diuretic hydrochlorothiazide (HCTZ).

5. The composition according to claims 1 to 3, characterised in that the hydrochlorothiazide is present in an amount of 10-15 mg or 20-30 mg.

6. The composition according to claims 1 to 3, characterised in that the sodium salt of telmisartan is present in an amount of 60-90 mg.

7. The composition according to claim 8, characterised in that the sodium salt of telmisartan is present in an amount of 80-85 mg.

8. The composition according to claims 1 to 3, characterised in that the sodium salt of telmisartan is present in an amount of 30-60 mg.

9. The composition according to claim 8, characterised in that the sodium salt of telmisartan is present in an amount of 40-45 mg.

10. The composition according to claims 7 and 9, characterised in that hydrochlorothiazide is present in an amount of 12-13 mg or 24-26 mg.

11. The composition according to claim 1, characterised in that the active substances is present together with the excipients sorbitol and magnesium stearate, compressed directly into tablets.

12. The composition according to claim 1, characterised in that the active substances are present as compressed dry granules of the telmisartan sodium salt containing the excipients mannitol, magnesium stearate and hydroxypropylcellulose with a mixture of hydrochlorothiazide, mannitol, microcrystalline cellulose and sodium glycol starch.

13. The composition according to claim 1, characterised in that the telmisartan sodium salt is formulated with additional pharmaceutically active substances.

14. Process for preparing the pharmaceutical composition according to claims 1 to 3, characterised in that the active substances are compressed with the excipients to form tablets.