WO2014091263A1 - Telmisartan containing pharmaceutical composition - Google Patents

Telmisartan containing pharmaceutical composition Download PDF

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Publication number
WO2014091263A1
WO2014091263A1 PCT/HU2013/000120 HU2013000120W WO2014091263A1 WO 2014091263 A1 WO2014091263 A1 WO 2014091263A1 HU 2013000120 W HU2013000120 W HU 2013000120W WO 2014091263 A1 WO2014091263 A1 WO 2014091263A1
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WO
WIPO (PCT)
Prior art keywords
telmisartan
weight
isomalt
pharmaceutical composition
sorbitol
Prior art date
Application number
PCT/HU2013/000120
Other languages
French (fr)
Inventor
László WAGNER
Zsolt Zsigmond
György UJFALUSSY
Adám ORBAN
Ágnes FÜLÖP
Original Assignee
Egis Pharmaceuticals Public Limited Company
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Publication of WO2014091263A1 publication Critical patent/WO2014091263A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising telmisartan as active ingredient, an alkalizer, a binder, a lubricant and isomaltose and to a process for the preparation thereof.
  • telmisartan is an active ingredient useful in the treatment of essential high pressure and also for the prevention of cardiovascular problems /e.g. myocardial attack, stroke/.
  • telmisartan in EP 1467712 two layer tablets comprising telmisartan and HCTZ /hydrochlorothiazide/ are disclosed.
  • One of the layers contains substantially amorphous telmisartan dissolved in a soluble matrix, while the other layer contains HCTZ in a disintegrating matrix.
  • the soluble matrix which contains the telmisartan comprises additionally an alkaline substance, a water soluble filler and optionally further auxiliary agents.
  • the alkaline substance may be an alkali hydroxide -e.g. sodium hydroxide or potassium hydroxide -, a basic amino acid -e.g.arginine, lysine - or meglumine.
  • suitable water soluble fillers which compensate the low solubility of telmisartan the following substances are mentioned: carbohydrates e.g. monosaccharides such as glucose; oligosaccharides such as saccharose, anhydrous lactose and lactose monohydrate; sugar alcohols e.g. sorbitol, mannitol, dulcitol, rhibitol and xylitol. Stress is laid on the importance of sorbitol as a particularly preferable representative of the water soluble fillers.
  • carbohydrates e.g. monosaccharides such as glucose
  • oligosaccharides such as saccharose, anhydrous lactose and lactose monohydrate
  • sugar alcohols e.g. sorbitol, mannitol, dulcitol, rhibitol and xylitol. Stress is laid on the importance of sorbitol as a particularly preferable representative of the water soluble fillers.
  • suitable hardness relates to a value above 100N, preferably above 130N.
  • the inventors referred to EP 1467712 and therefore carried out the experiments with sorbitol as selected sugar alcohol in order to produce tablets of suitable hardness.
  • the inventors found it as surprising that the hardness of the tablets depends on the specific surface rather than on the particle size of sorbitol.
  • suitable tablets hardness can be achieved with a specific surface of sorbitol of 0.75-3.5 m 2 /g, preferably 1.4-3.0 m 2 /g, particularly preferably 2.0-2.5 m 2 /g.
  • telmisartan can be significantly increased and in the place of the expensive and circumstantial powder drying the cheaper and more simple fluidization granulation can be used for the preparation of the telmisartan tablets.
  • the following water soluble fillers are enumerated: carbohydrates e.g. glucose; oligosaccharides e.g. sacharose; and sugar alcohols e.g. erithritol, sorbitol, mannitol, dulcitol, sorbitol and xylitol. Stress is laid on mannitol, erythritol, sorbitol and saccharose as particularly suitable water soluble fillers
  • telmisartan and HCTZ containing two layer tablets are prepared also by fluidization granulation and hereby a surfactant or emulsifier is used.
  • One layer of the tablet contains the telmisartan and the other the HCTZ in a disintegrating matrix.
  • telmisartan a tablet comprising telmisartan, sodium hydroxide, PVP, lactose monohydrate, crospovidone, meglumine, magnesium stearate and water is disclosed; the tablet contains no surfactant.
  • the two layer tablet set forth in IN 2009/MU02745 comprises no surfactant in the telmisartan containing layer and no disintegrant in the HCTZ containing layer.
  • the telmisartan is prepared by a process other than powder drying.
  • a telmisartan composition is disclosed which contains neither a surfactant, nor an emulsifier and is prepared by using the cheaper and more simple fluidization granulation in place of the powder drying.
  • the following fillers are enumerated: saccharose , lactose, mannitol, xylitol, sorbitol, maltitol, lactitol, erythritol, isomalt and mixtures thereof.
  • sorbitol Exemplified are sorbitol, mannitol, saccharose and lactose while sorbitol is mentioned as particularly preferable filler.
  • the reason thereof is that -compared to mannitol, saccharose and lactose - the use of sorbitol provides a higher total yield, the composition can be more readily tabletted and the tablets obtained are less brittle.
  • telmisartan containing composition crystalline telmisartan is dissolved in the aqueous solution of sodium hydroxide and meglumine, and thereafter Povidon K25 is added to the solution in order to stabilize the amorphous state of telmisartan.
  • the solution obtained is subjected to spray-drying in a drying column. This procedure results in the formation of an amorphous telmisartan powder.
  • the amorphous telmisartan is homogenized first with sorbitol and thereafter with magnesium stearate and finally pressed into tablets.
  • the drawback of the powder drying process is that the apparatus can be used only for this purpose and further equipment is required for the preparation of the product. Additionally the technology is energy intensive and a higher temperature must be used as compared to the fluidization granulation apparatus..
  • An object of the invention is the preparation of a telmisartan containing tablet composition which is resistant to the moisture content of the air and is therefore stable for a significantly longer period of time than the sorbitol containing tablets -s.g. Micardis -, and is bioequivalent with the tablets of the originator.
  • a further object of the invention is the elaboration of a simple high yield process for the preparation of the above telmisartan containing composition which is cheaper than powder drying.
  • Such a less hygroscopic tablet which resists to a higher extent to the moisture content of air can be packaged in a much more simple and cheaper way and this constitutes a further advantage.
  • telmisartan containing solution can be used to replace powder drying by spraying the telmisartan containing solution onto the isomalt while omitting the use of a surfactant or an emulsifier;
  • the granulate obtained can be more readily pressed into tablets with smaller losses;
  • An object of the invention is a pharmaceutical composition
  • telmisartan as active ingredient, an alkalizer, a binder, a lubricant and isomalt.
  • the composition is free from a surfactant, an emulsifier and a disintegrant.
  • the composition contains as binder PVP and/or HPMC, preferably PVP.
  • the composition contains as lubricant magnesium stearate or sodium stearyl fumarate, preferably magnesium stearate.
  • the composition contains 10-20 % by weight, preferably 15-18 % by weight, particularly preferably 16.5 % by weight of telmisartan
  • the composition contains 60-86.7 % by weight, preferably 70-80 % by weight, particularly preferably 71 % by weight of isomalt.
  • the composition contains 10-20 % by weight, preferably 15-18 % by weight, particularly preferably 16.5 % by weight of telmisartan and 60-86.7 % by weight, preferably 70- 80 % by weight, particularly preferably 71 % by weight of isomalt.
  • a process for the preparation of a pharmaceutical composition which comprises dissolving the
  • telmisartan in the aqueous solution of the alkalizers, adding the solution of the binder, thereafter spraying the solution thus obtained onto the isomalt in a fluidization apparatus, homogenizing the granulate thus obtained with the lubricant and finally pressing the homogenized product into tablets.
  • neither a surfactant, nor an emulsifier not a disintegrant is used.
  • a surfactant nor an emulsifier not a disintegrant.
  • mannitol By way of experiment we have sprayed the telmisartan containing solution onto a mannitol containing fluid bed. We have chosen mannitol because this is a sugar alcohol chemically strictly related to sorbitol, it is considerably less water soluble and therefore it could be expected that mannitol would not be dissolved during granulation.
  • composition of the product thus obtained is as follows:
  • mannitol When using mannitol the problems occurring in the application of sorbitol did not take place i.e. mannitol was not dissolved in the granulating liquid even in case of a higher spraying speed of 7.2-7.8 g/min and the granulate particles formed did not stick together. However we have observed sticking or adhesion which made the tableting procedure more difficult and moreover a large number of waste tablets was formed. For this reason we have rejected the industrial scale use of mannitol.
  • microcrystalline cellulose as water insoluble auxiliary agent.
  • the fluidization granulation was successful, however the in vitro dissolution of the telmisartan composition prepared by using microcrystalline cellulose was very different from that of Micardis. Since due to this deviation the registration requirements relating to bioequivalence could not be fulfilled, we had to reject this solution as well.
  • the fluidization granulation of the telmisartan containing composition can be carried out by using a high spraying speed of 7.2-7.8 g min. even in the absence of a surfactant or an emulsifier.
  • the granules formed can be pressed to tablets in a significantly safer manner.
  • the easier tabletting manifests itself in two important respects.
  • a smaller number of waste tablets is formed; the yield of the isomalt technology is higher by 15 % than that of the mannitol procedure.
  • the surface of the tablets obtained by the isomalt procedure is more shining and no lubrication error occurs as happened in case of the mannitol containing tablets.
  • Isomalt is a disaccharide belonging into the group sugar alcohols and consisting of gluccopyranosyl-sorbitol /GPS/ and glucopyranosyl-mannitol /GPM .
  • the GPS:GPM ratio is 1 :1 .
  • Isomalt is a sugar alcohol of outstanding morphology, it consists of amorphous particles, is not polymorph, accordingly polymorph transformation is not to be feared with the progress of time.
  • the large specific surface of the amorphous particles guarantees a homogenous admixture of the active ingredient and the other active ingredients and no subsequent segregation takes place.
  • a further advantage resides in the fact that when using isomalt in the preparation of the telmisartan composition a disintegrant can be omitted because the tablets obtained possess outstanding dissolution and disintegration properties, If no disintegrant is used the composition of the tablet is more simple, the preparation of the tablets is more economical, better and also the load of the human organism by superfluous inactive synthetic substances is decreased.
  • the inorganic base content of the invention composition amounts to 1-2 % by weight, preferably 1.3-1.7 % by weight and particularly preferably 1.5 % by weight.
  • the organic base content of our composition is 1-10 % by weight preferably 4-8 % by weight and particularly preferably 5 % by weight.
  • the binder content of the our composition is 1-10 % by weight, preferably 4-8 % by weight and particularly preferably 5 % by weight.
  • the lubricant content of our composition is 0.3-2.0 % by weight, preferably 0.8-1.5 % by weight, particularly preferably 1 % by weight.
  • test conditions were as follows: The compositions were allowed to stand in Petri dishes, at 40°C and a relative moisture content of 75 % by weight for 4 weeks, in accordance with the Directive ICH Q1A R2/.
  • the percental water uptake of the Micardis composition is identical with that of sorbitol /31-32 %/ within the margin of error. Additionally since sorbitol is a high hygroscopic substance, the Micardis composition absorbs a large amount of water from the air. This is the reason why the Micardis compositions are put on the market in a three layer /OPA/PVC/ so-called "cold blister" packaging which protects the tablets from moistening and liquefying due to the effect of the moisture content of the air.
  • mannitol does not practically absorb water and the water absorption of the isomalt containing telmisartan compositions of the invention is about 6.5 % i.e. only one- fifth of that of the Micardis compositions.
  • the results of the above test are demonstrated in a spectacular manner on Figures 3-5 by showing the condition of sorbitol, isomalt and telmisartan compositions containing sorbitol and isomalt, respectively after 4 weeks of storage.
  • Figure 3 shows the condition of GalenIQ800 /isomalt/. It can be seem that under such conditions isomalt keeps its powder form.
  • Figure 4 shows the condition of sorbitol. The Figure clearly demonstrates that under the above conditions sorbitol is moistened under the effect of the moisture content of air and is fully liquefied.
  • Figure 5 shows the condition of tablets prepared by us containing GalenlQ 800 /isomalt/ and 40 mg of telmisartan in four Petri dishes. The left rear Figure shows the condition of our tablets comprising GalenlQ 800 /isomalt/ and 40 mg of telmisartan.
  • the left front Figure presents the condition of the tablets prepared by us, containing GalenlQ 800 /isomalt/ and 80 mg of telmisartan active ingredient.
  • the right rear shows the condition of the Micardis tablets containing sorbitol and 40 mg of telmisartan active ingredient; while the right front Figure shows the condition of Micardis tablets containing sorbitol and 80 mg of telmisartan.
  • Figure 6 presents a comparison of the dissolution /in a phosphate buffer,pH 7.5/ of the Micardis tablet comprising 80 mg of telmisartan and sorbitol with the isomalt containing telmisartan tablet according to the present invention.
  • the test conditions were as follows: the dissolving liquid /phosphate buffer/ was stirred with a paddle, at 75 rpm.
  • Moisture content not more than 7.0 %
  • Active ingredient content 95.0-105.0 %
  • compositions meet the requirements
  • the three layer Cold blister packaging provides a better protection against the moisture content of the air than the two layer PVC/PVdC packaging;
  • the active ingredient content of the mannitol containing tablets decreased with the progress of time in both the Cold blister and the two layer PVC/PVdC packaging, while on the other hand the active ingredient content of the isomalt containing invention tablets did not decrease in said packaging after the storing period of 4 weeks;
  • the invention composition shows an in vitro dissolution equivalent with that of the Micardis tablet of the originator.
  • the invention composition is not as strongly hygroscopic as the Micardis tablet, therefore our composition remains more stable than the sorbitol containing product for a significantly longer period of time and this enables the substitution of the expensive Cold blister packaging by a much cheaper packaging material, or -alternatively -if Cold blister is used, the shelf-time will lengthen.
  • the composition can be prepared in a fluidization granulating equipment generally used in pharmaceutical industry.
  • the granulate can be prepared directly after dissolving of the telmisartan and this results in a saving of energy; additionally fluidization is carried out at a lower temperature than powder drying which represents a saving of time since the homogenization step with sorbitol can be omitted.
  • fluidization granulation is performed with isomalt as filler -contrary to the use of sorbitol - there is no risk of the in situ dissolving of the isomalt filler. For this reason the telmisartan solution can be sprayed onto the isomalt with a higher spraying speed and this enables a rapid granulating step.
  • Fluidization granulation can be carried without using a surfactant and an emulsifier.
  • the technology is rendered more simple and the load of the human organism with pharmaceutically inactive excipients is reduced.
  • the preparation of the telmisartan composition does not require the use of a disintegrant because the isomalt containing tablets possess outstanding dissolution and disintegrating properties.
  • a further advantage of the isomalt containing invention compositions over the tablets containing sorbitol and mannitol is that it can be pressed more readily into tablets, because identical pressing strength provides higher tablet strength and better wear resistance.
  • the isomalt containing granules can be more easily pressed and with less losses than the sorbitol and mannitol containing granules and therefore - contrary to the use of sorbitol - there is no need of the use of a special specific surface variant.

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Abstract

The invention relates to a pharmaceutical compositions comprising telmisartran as active ingredient, an alkalizer, a binder, a lubricant and isomalt. The invention also relates to a process for the preparation of the above pharmaceutical compositions which comprises dissolving telmisartan in the aqueous solution of the alkalizers, thereafter adding the solution of the binder, spraying the solution thus obtained in a fluidization apparatus onto the isomalt, homogenizing the granulated thus obtained with the lubricant and pressing the homogenized product obtained to tablets. In the invention process neither a surfactant, nor an emulsifiers nor a disintegrant is used.

Description

TELMISARTAN CONTAINING PHARMACEUTICAL COMPOSITION
The present invention relates to a pharmaceutical composition comprising telmisartan as active ingredient, an alkalizer, a binder, a lubricant and isomaltose and to a process for the preparation thereof.
It is known that telmisartan is an active ingredient useful in the treatment of essential high pressure and also for the prevention of cardiovascular problems /e.g. myocardial attack, stroke/.
Telmisartan of the Formula 1 was disclosed for the first time in EP 502314
Figure imgf000002_0001
In EP 1467712 two layer tablets comprising telmisartan and HCTZ /hydrochlorothiazide/ are disclosed. One of the layers contains substantially amorphous telmisartan dissolved in a soluble matrix, while the other layer contains HCTZ in a disintegrating matrix. The soluble matrix which contains the telmisartan comprises additionally an alkaline substance, a water soluble filler and optionally further auxiliary agents. According to said patent specification the alkaline substance may be an alkali hydroxide -e.g. sodium hydroxide or potassium hydroxide -, a basic amino acid -e.g.arginine, lysine - or meglumine. As suitable water soluble fillers which compensate the low solubility of telmisartan the following substances are mentioned: carbohydrates e.g. monosaccharides such as glucose; oligosaccharides such as saccharose, anhydrous lactose and lactose monohydrate; sugar alcohols e.g. sorbitol, mannitol, dulcitol, rhibitol and xylitol. Stress is laid on the importance of sorbitol as a particularly preferable representative of the water soluble fillers.
The key feature of the invention described in EP 2120884 is the preparation of a telmisartan tablet of suitable hardness. The term "suitable hardness" relates to a value above 100N, preferably above 130N. The inventors referred to EP 1467712 and therefore carried out the experiments with sorbitol as selected sugar alcohol in order to produce tablets of suitable hardness. The inventors found it as surprising that the hardness of the tablets depends on the specific surface rather than on the particle size of sorbitol. According to said patent specification suitable tablets hardness can be achieved with a specific surface of sorbitol of 0.75-3.5 m2/g, preferably 1.4-3.0 m2/g, particularly preferably 2.0-2.5 m2/g.
The essence of EP 1545467 is that by using a surfactant or emulsifier the solubility of telmisartan can be significantly increased and in the place of the expensive and circumstantial powder drying the cheaper and more simple fluidization granulation can be used for the preparation of the telmisartan tablets. The following water soluble fillers are enumerated: carbohydrates e.g. glucose; oligosaccharides e.g. sacharose; and sugar alcohols e.g. erithritol, sorbitol, mannitol, dulcitol, sorbitol and xylitol. Stress is laid on mannitol, erythritol, sorbitol and saccharose as particularly suitable water soluble fillers
Also according to EP 17997872 surfactants are used in telmisartan containing compositions, however here a different so-called "high shear mixing" technology is applied.
According to WO 2007/060170 telmisartan and HCTZ containing two layer tablets are prepared also by fluidization granulation and hereby a surfactant or emulsifier is used. One layer of the tablet contains the telmisartan and the other the HCTZ in a disintegrating matrix.
In IN 2007/MU/01584 a tablet comprising telmisartan, sodium hydroxide, PVP, lactose monohydrate, crospovidone, meglumine, magnesium stearate and water is disclosed; the tablet contains no surfactant.
The two layer tablet set forth in IN 2009/MU02745 comprises no surfactant in the telmisartan containing layer and no disintegrant in the HCTZ containing layer. The telmisartan is prepared by a process other than powder drying. In WO 2009/135646 a telmisartan composition is disclosed which contains neither a surfactant, nor an emulsifier and is prepared by using the cheaper and more simple fluidization granulation in place of the powder drying. The following fillers are enumerated: saccharose , lactose, mannitol, xylitol, sorbitol, maltitol, lactitol, erythritol, isomalt and mixtures thereof. Exemplified are sorbitol, mannitol, saccharose and lactose while sorbitol is mentioned as particularly preferable filler. The reason thereof is that -compared to mannitol, saccharose and lactose - the use of sorbitol provides a higher total yield, the composition can be more readily tabletted and the tablets obtained are less brittle.
In EP 1467712 the originator gives the following teaching for the preparation of the telmisartan containing composition: crystalline telmisartan is dissolved in the aqueous solution of sodium hydroxide and meglumine, and thereafter Povidon K25 is added to the solution in order to stabilize the amorphous state of telmisartan. The solution obtained is subjected to spray-drying in a drying column. This procedure results in the formation of an amorphous telmisartan powder. The amorphous telmisartan is homogenized first with sorbitol and thereafter with magnesium stearate and finally pressed into tablets.
The drawback of the powder drying process is that the apparatus can be used only for this purpose and further equipment is required for the preparation of the product. Additionally the technology is energy intensive and a higher temperature must be used as compared to the fluidization granulation apparatus..
The general conception of the above-cited EP 1467712, EP 2120884 and WO 2009/135646, which form the state of the art, is that sorbitol is considered to be particularly preferable and is used in the Micardis composition of the originator. However sorbitol can only be applied in a three-layer impermeable protecting packaging because of the highly hygroscopic character thereof. Otherwise the composition would soon disintegrate under the effect of the moisture content of the air.
Object of the invention
An object of the invention is the preparation of a telmisartan containing tablet composition which is resistant to the moisture content of the air and is therefore stable for a significantly longer period of time than the sorbitol containing tablets -s.g. Micardis -, and is bioequivalent with the tablets of the originator. A further object of the invention is the elaboration of a simple high yield process for the preparation of the above telmisartan containing composition which is cheaper than powder drying.
Such a less hygroscopic tablet which resists to a higher extent to the moisture content of air can be packaged in a much more simple and cheaper way and this constitutes a further advantage.
On working out the present invention we were surprised to find that when using isomalt as water soluble filler by the preparation of the telmisartan containing composition
- fluidization granulation can be used to replace powder drying by spraying the telmisartan containing solution onto the isomalt while omitting the use of a surfactant or an emulsifier;
the granulate obtained can be more readily pressed into tablets with smaller losses;
- the stability of the composition on air is significantly better than that of the referent composition Micardis,
- our product shows an equivalent in vitro dissolution with the Micardis composition of the originator; accordingly the object of the registration procedure -namely the bioequivalence -can be achieved.
Detailed description of the invention
An object of the invention is a pharmaceutical composition comprising telmisartan as active ingredient, an alkalizer, a binder, a lubricant and isomalt.
According to a preferred embodiment of the pharmaceutical composition of the the present invention the composition is free from a surfactant, an emulsifier and a disintegrant.
According to a further preferred embodiment of the pharmaceutical composition according to the present invention the composition contains as binder PVP and/or HPMC, preferably PVP.
According to a further preferred embodiment of the pharmaceutical composition according to the present invention the composition contains as lubricant magnesium stearate or sodium stearyl fumarate, preferably magnesium stearate. According to a further preferred embodiment of the pharmaceutical composition according to the present invention the composition contains 10-20 % by weight, preferably 15-18 % by weight, particularly preferably 16.5 % by weight of telmisartan
According to a further preferred embodiment of the pharmaceutical composition according to the present invention the composition contains 60-86.7 % by weight, preferably 70-80 % by weight, particularly preferably 71 % by weight of isomalt. According to a further preferred embodiment of the pharmaceutical composition according to the present invention the composition contains 10-20 % by weight, preferably 15-18 % by weight, particularly preferably 16.5 % by weight of telmisartan and 60-86.7 % by weight, preferably 70- 80 % by weight, particularly preferably 71 % by weight of isomalt. According to the present invention there is also provided a process for the preparation of a pharmaceutical composition which comprises dissolving the
telmisartan in the aqueous solution of the alkalizers, adding the solution of the binder, thereafter spraying the solution thus obtained onto the isomalt in a fluidization apparatus, homogenizing the granulate thus obtained with the lubricant and finally pressing the homogenized product into tablets.
According to a preferred embodiment of the process of the present invention neither a surfactant, nor an emulsifier not a disintegrant is used. Considering the teaching according to EP 1545467 one could expect that when using sugar alcohols as water soluble filler a telmisartan containing pharmaceutical composition can be prepared by fluidization granulation only by adding a surfactant or an emulsifier.
Said expectation has been strengthened by our own experiments showing that -contrary to the teaching of WO 2009/1354646 - the high water solubility of sorbitol made the production of the granulate in a fluidization apparatus very circumstantial because sorbitol was partially dissolved under the effect of the granulating liquid. For this reason the telmisartan solution could be sprayed onto the sorbitol containing fluid bed only by applying a very low addition rate and a spraying speed of 3.2-3.8 g/minute. Even the granule particle thus obtained can easily stick to large lumps.
By way of experiment we have sprayed the telmisartan containing solution onto a mannitol containing fluid bed. We have chosen mannitol because this is a sugar alcohol chemically strictly related to sorbitol, it is considerably less water soluble and therefore it could be expected that mannitol would not be dissolved during granulation.
The composition of the product thus obtained is as follows:
Figure imgf000007_0001
When using mannitol the problems occurring in the application of sorbitol did not take place i.e. mannitol was not dissolved in the granulating liquid even in case of a higher spraying speed of 7.2-7.8 g/min and the granulate particles formed did not stick together. However we have observed sticking or adhesion which made the tableting procedure more difficult and moreover a large number of waste tablets was formed. For this reason we have rejected the industrial scale use of mannitol.
We have also tried to use microcrystalline cellulose as water insoluble auxiliary agent. In accordance with our expectation the fluidization granulation was successful, however the in vitro dissolution of the telmisartan composition prepared by using microcrystalline cellulose was very different from that of Micardis. Since due to this deviation the registration requirements relating to bioequivalence could not be fulfilled, we had to reject this solution as well.
On Figure 1 the dissolution in 0.1 M hydrochloric acid of the 80 mg, sorbitol containing Micardis tablets and that of the tablets prepared by us containing microcrystalline cellulose was compared. During tableting the pressing strength was 4 kN and two parallel tests were carried out. The test conditions were as follows: the dissolving liquid /0.1 M hydrochloric acid/ was stirred with a paddle, rotating velocity 75 rpm. It can be seen from Figure 1 that the dissolution profile of the telmisartan tablets prepared by us and containing microcrystalline cellulose differ significantly from that of the Micardis tablets.
On Figure 2 the dissolution profile /pH 7.5, in a phosphate buffer/ of the 80 mg Micardis tablet containing sorbitol and the telmisartan tablets prepared by us and containing microcrystalline cellulose was compared. In course of tabletting the pressing strength was 4 kN and two parallel dissolution tests were carried out. The following test conditions were used: the dissolution liquid /phosphate buffer/ was stirred with a paddle at 75 rpm.
It can be seen from the Figure that the dissolution profile of the telmisartan tablets prepared by us and containing microcrystalline cellulose and that of the Micardis tablet's are significantly different.
After performing our above tests we have surprisingly found that all of the above drawbacks can be overcome by using isomalt as water soluble filler.
- The fluidization granulation of the telmisartan containing composition can be carried out by using a high spraying speed of 7.2-7.8 g min. even in the absence of a surfactant or an emulsifier.
- There is no disturbing sticking or adhesion, the granules formed can be pressed to tablets in a significantly safer manner. The easier tabletting manifests itself in two important respects. On the one hand a smaller number of waste tablets is formed; the yield of the isomalt technology is higher by 15 % than that of the mannitol procedure. On the other hand the surface of the tablets obtained by the isomalt procedure is more shining and no lubrication error occurs as happened in case of the mannitol containing tablets.
Isomalt is a disaccharide belonging into the group sugar alcohols and consisting of gluccopyranosyl-sorbitol /GPS/ and glucopyranosyl-mannitol /GPM . In case of the GalenlQQ 800 used by us /manufacturer: Beneo-Palatinit/, the GPS:GPM ratio is 1 :1 . Isomalt is a sugar alcohol of outstanding morphology, it consists of amorphous particles, is not polymorph, accordingly polymorph transformation is not to be feared with the progress of time. The large specific surface of the amorphous particles guarantees a homogenous admixture of the active ingredient and the other active ingredients and no subsequent segregation takes place. A further advantage resides in the fact that when using isomalt in the preparation of the telmisartan composition a disintegrant can be omitted because the tablets obtained possess outstanding dissolution and disintegration properties, If no disintegrant is used the composition of the tablet is more simple, the preparation of the tablets is more economical, better and also the load of the human organism by superfluous inactive synthetic substances is decreased.
In Table 1 the water solubility of three auxiliary agents - mannitol, isomalt and sorbitol - is shown:
Table 1
Figure imgf000009_0001
(Source: * Handbook of Pharmaceutical Excipients, Sixth Edition
** Hungarian Wikipedia
*** German Wikipedia)
The data of Table 1 show that both isomalt and mannitol used as comparative material readily soluble in water, but are less soluble than sorbitol used in the product of the originator.
The details of the present invention are illustrated by the following Example.
Preparation of our isomalt containing telmisartan composition In a solution of 7 mg of sodium hydroxide, 24 mg of meglumine and 225 mg of waster 80 mg of telmisartan are dissolved whereupon a solution of 24 mg of Povidone and 100 mg of water is added. The solution thus obtained is sprayed onto 340 mg of isomalt in a fluidization apparatus. The granulate thus obtained is homogenized with 5 mg of magnesium stearate and pressed into tablets. The composition of our product thus obtained is as follows:
Figure imgf000010_0001
The inorganic base content of the invention composition amounts to 1-2 % by weight, preferably 1.3-1.7 % by weight and particularly preferably 1.5 % by weight. The organic base content of our composition is 1-10 % by weight preferably 4-8 % by weight and particularly preferably 5 % by weight. The binder content of the our composition is 1-10 % by weight, preferably 4-8 % by weight and particularly preferably 5 % by weight. The lubricant content of our composition is 0.3-2.0 % by weight, preferably 0.8-1.5 % by weight, particularly preferably 1 % by weight.
Comparative test
The test conditions were as follows: The compositions were allowed to stand in Petri dishes, at 40°C and a relative moisture content of 75 % by weight for 4 weeks, in accordance with the Directive ICH Q1A R2/.
The hygroscopic properties of telmisartan compositions containing three auxiliary agents - isomalt, sorbitol and mannitol - were compared. The results of the test are shown in Table 2. Table 2
Figure imgf000011_0001
It can be seen from the values of Table 2 that the percental water uptake of the Micardis composition is identical with that of sorbitol /31-32 %/ within the margin of error. Additionally since sorbitol is a high hygroscopic substance, the Micardis composition absorbs a large amount of water from the air. This is the reason why the Micardis compositions are put on the market in a three layer /OPA/PVC/ so-called "cold blister" packaging which protects the tablets from moistening and liquefying due to the effect of the moisture content of the air.
Contrary to sorbitol, mannitol does not practically absorb water and the water absorption of the isomalt containing telmisartan compositions of the invention is about 6.5 % i.e. only one- fifth of that of the Micardis compositions. The results of the above test are demonstrated in a spectacular manner on Figures 3-5 by showing the condition of sorbitol, isomalt and telmisartan compositions containing sorbitol and isomalt, respectively after 4 weeks of storage.
Figure 3 shows the condition of GalenIQ800 /isomalt/. It can be seem that under such conditions isomalt keeps its powder form. Figure 4 shows the condition of sorbitol. The Figure clearly demonstrates that under the above conditions sorbitol is moistened under the effect of the moisture content of air and is fully liquefied. Figure 5 shows the condition of tablets prepared by us containing GalenlQ 800 /isomalt/ and 40 mg of telmisartan in four Petri dishes. The left rear Figure shows the condition of our tablets comprising GalenlQ 800 /isomalt/ and 40 mg of telmisartan. The left front Figure presents the condition of the tablets prepared by us, containing GalenlQ 800 /isomalt/ and 80 mg of telmisartan active ingredient. The right rear shows the condition of the Micardis tablets containing sorbitol and 40 mg of telmisartan active ingredient; while the right front Figure shows the condition of Micardis tablets containing sorbitol and 80 mg of telmisartan.
It is clearly visible that the left-side tablets containing isomalt kept their original form. On the other hand the right side Micardis tablets containing sorbitol moistened, became partially liquid and lost their discrete tablet form.
Figure 6 presents a comparison of the dissolution /in a phosphate buffer,pH 7.5/ of the Micardis tablet comprising 80 mg of telmisartan and sorbitol with the isomalt containing telmisartan tablet according to the present invention.The test conditions were as follows: the dissolving liquid /phosphate buffer/ was stirred with a paddle, at 75 rpm.
It clearly appears from Figure 6 that the dissolution profiles of the invention telmisartan tablet which contains isomalt as filler andthat ofthe Micardis tablet are in good agreement. In Table 3 the change of the moisture content, breaking strength and dissolution of telmisartan tablets containing mannitol and isomalt, respectively are shown, in accordance with the Directive ICH Q1A R2/. The compositions were packed in three different packaging materials, namely a two layer PVC/PVdC blister packaging, a silica gel containing brown glass and a three layer Cold blister packaging respectively. Storing period: 4 weeks. Table 3
Figure imgf000013_0001
The suitability requirements of the composition are as follows:
Moisture content: not more than 7.0 %
Breaking strength: at least 40N
Active ingredient content: 95.0-105.0 %
Dissolution: at pH 3.5, after 30 minutes at least 80 % /Q=75%/.
From the results of Table 3 one can draw the following conclusions:
- after storing for 4 weeks in the different packaging materials the compositions meet the requirements;
- the three layer Cold blister packaging provides a better protection against the moisture content of the air than the two layer PVC/PVdC packaging; the active ingredient content of the mannitol containing tablets decreased with the progress of time in both the Cold blister and the two layer PVC/PVdC packaging, while on the other hand the active ingredient content of the isomalt containing invention tablets did not decrease in said packaging after the storing period of 4 weeks;
- the breaking strength of the mannitol containing tablets in the PVC/PVdC blister packaging increased to a larger extent than that of the isomalt containing tablets according to the invention.
The advantages of the isomalt containing invention compositions are substantiated by all of the following characteristics :
The invention composition shows an in vitro dissolution equivalent with that of the Micardis tablet of the originator. At the same time the invention composition is not as strongly hygroscopic as the Micardis tablet, therefore our composition remains more stable than the sorbitol containing product for a significantly longer period of time and this enables the substitution of the expensive Cold blister packaging by a much cheaper packaging material, or -alternatively -if Cold blister is used, the shelf-time will lengthen.
The composition can be prepared in a fluidization granulating equipment generally used in pharmaceutical industry. The granulate can be prepared directly after dissolving of the telmisartan and this results in a saving of energy; additionally fluidization is carried out at a lower temperature than powder drying which represents a saving of time since the homogenization step with sorbitol can be omitted. When fluidization granulation is performed with isomalt as filler -contrary to the use of sorbitol - there is no risk of the in situ dissolving of the isomalt filler. For this reason the telmisartan solution can be sprayed onto the isomalt with a higher spraying speed and this enables a rapid granulating step. Fluidization granulation can be carried without using a surfactant and an emulsifier. Thus the technology is rendered more simple and the load of the human organism with pharmaceutically inactive excipients is reduced. The preparation of the telmisartan composition does not require the use of a disintegrant because the isomalt containing tablets possess outstanding dissolution and disintegrating properties.
A further advantage of the isomalt containing invention compositions over the tablets containing sorbitol and mannitol is that it can be pressed more readily into tablets, because identical pressing strength provides higher tablet strength and better wear resistance. The isomalt containing granules can be more easily pressed and with less losses than the sorbitol and mannitol containing granules and therefore - contrary to the use of sorbitol - there is no need of the use of a special specific surface variant.

Claims

Claims
1. Pharmaceutical composition comprising telmisartan active ingredient, an alkalizer, a binder, a lubricant and isomalt.
2. Pharmaceutical composition according to Claim 1 which is free from a surfactant, an emulsifier and a disintegrant.
3. Pharmaceutical composition according to Claim 1 or 2 which comprises PVP and/or HPMC, preferably PVP as binder.
4. Pharmaceutical composition according to any of Claims 1-3 which comprises magnesium stearate, or sodium stearyl fumarate, preferably magnesium stearate as lubricant.
5. Pharmaceutical composition according to any of Claims 1-4 which comprises 10-20 % by weight, preferably 15-18 % by weight, particularly preferably 16.5 % by weight of telmisartan.
6. Pharmaceutical composition according to any of Claims 1-5 which comprises 60-86.7 % by weight, preferably 70-80 % by weight, particularly preferably 71% by weight of isomalt.
7. Pharmaceutical composition according to any of Claims 1-4 which comprises 10-20 by weight, preferably 15-18 % by weight, particularly preferably 16.5 % by weight of telmisartan and 60-86.7 % by weight, preferably 70-80 % by weight, particularly preferably 71 % by weight of isomalt.
8. Process for the preparation of a pharmaceutical composition according to any of Claims 1-7 which comprises dissolving telmisartan in the aqueous solution of the alkalizers , adding the solution of the binder, spraying the solution thus obtained onto the isomalt in a fluidizing apparatus, homogenising the granulate thus obtained with the lubricant and finally tabletting the homogenized mixture. Process according to claim 8 which comprises using neither a surfactant, emulsifier, nor a disintegrant.
PCT/HU2013/000120 2012-12-11 2013-12-10 Telmisartan containing pharmaceutical composition WO2014091263A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017520631A (en) * 2014-07-30 2017-07-27 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Orally disintegrating tablets
CN112870174A (en) * 2021-02-08 2021-06-01 天方药业有限公司 Preparation method of telmisartan tablets

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009135646A2 (en) * 2008-05-05 2009-11-12 Farmaprojects, Sa Stable pharmaceutical compositions and their processes for preparation suitable for industrial scale
WO2010137855A2 (en) * 2009-05-27 2010-12-02 Dasan Medichem Co., Ltd. Multi-layer tablet comprising effervescent layer
WO2012055941A1 (en) * 2010-10-27 2012-05-03 Krka,Tovarna Zdravil, D. D., Novo Mesto Multilayer pharmaceutical composition comprising telmisartan and amlodipine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009135646A2 (en) * 2008-05-05 2009-11-12 Farmaprojects, Sa Stable pharmaceutical compositions and their processes for preparation suitable for industrial scale
WO2010137855A2 (en) * 2009-05-27 2010-12-02 Dasan Medichem Co., Ltd. Multi-layer tablet comprising effervescent layer
WO2012055941A1 (en) * 2010-10-27 2012-05-03 Krka,Tovarna Zdravil, D. D., Novo Mesto Multilayer pharmaceutical composition comprising telmisartan and amlodipine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017520631A (en) * 2014-07-30 2017-07-27 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Orally disintegrating tablets
US9789059B2 (en) 2014-07-30 2017-10-17 Boehringer Ingelheim International Gmbh Oral disintegrating tablet
US10918595B2 (en) 2014-07-30 2021-02-16 Boehringer Ingelheim International Gmbh Oral disintegrating tablet
CN112870174A (en) * 2021-02-08 2021-06-01 天方药业有限公司 Preparation method of telmisartan tablets

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