EA008063B1 - Valsartan containing formulation - Google Patents

Abstract

A pharmaceutical containing valsartan, optionally a combination of valsartan with hydrochlorothiazide, obtainable by direct tabletting, comprises a filler having a particle size of 10 to 1000 m, preferably 50 to 400 mkm, in amounts of 20 to 60, preferably 40 to 60% by weight, based on the total weight of the formulation.

Description

FIELD OF THE INVENTION

The present invention relates to a tablet containing the active substance valsartan, optionally in combination with hydrochlorothiazide, prepared by direct tabletting.

State of the art

Valsartan, a compound having the chemical name H- (1-oxopentyl) -H - [[2 '- (1H-tetrazol-5yl) [1,1'-biphenyl] -4-yl] methyl] -E-valine of formula I

belongs to the group of drugs that block angiotensin II receptors and thereby cause a decrease in blood pressure. These substances are used to treat arterial hypertension and chronic heart failure.

Valsartan and related compounds with an affinity for angiotensin II receptors are described in US Pat. No. 5,399,578. The dosage form described in the patent contains the following components:

Active substance 100 mg Lactose 100 mg Corn starch 70 mg Talc 8.5 g Calcium stearate 1, 5 mg Hydroxypropyl methylcellulose 2.36 mg Shellac 0.64 g

The mixture containing the active substance, lactose and part of the corn starch is granulated by wet granulation and, after drying, mixed with the remaining starch, calcium stearate and talc, and then pressed into tablets.

According to the application for international patent \ kO 95/24901 the dosage in the form of a capsule has the following composition:

Valsartan 80 mg Microcrystalline cellulose 110 mg Polyvidone KZO 45.2 mg Sodium Lauryl Sulfate 1.2 mg Crospovidone 26 mg Magnesium stearate 2, 6 mg

The first two components are granulated by wet granulation in the presence of a solution of the third and fourth components in water. 5 and 6 components are introduced into the dry granulate and the capsules are filled with the resulting mixture.

However, as noted in the application XVO 97/49394, such previously described methods are characterized by low reproducibility, especially with regard to their compression into tablets. In the application under consideration, the wet granulation method is used to obtain valsartan tablets. In this case, the composition described in Xk'O 95/24901 is slightly changed.

Valsartan 80 mg Hydrochlorothiazide 12.5 mg Colloidal Silica ΑΕΒΟΒΙΕ 1.5 mg Microcrystalline cellulose 31.5 mg Crospovidone 20 mg Magnesium stearate 4,5 mg

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The first to fifth components are mixed and pressed at a pressure of 25-65 kN. The pressed material is then passed through a sieve. The granulate thus obtained is mixed with magnesium stearate and the resulting mixture is compressed into tablets.

An extraordinary advantage of the method disclosed in the cited application is the fact that for each special formulation it is possible to determine the necessary minimum sealing pressure in the pressure range 25-65 kN, as a result of which tablets are obtained that demonstrate a 6 times faster disintegration rate than the speed during normal sealing (i.e. when using high pressure).

A higher rate of disintegration of the tablets obtained by the considered method provides a higher rate of release of the active substance, its faster absorption in the body and, ultimately, higher bioavailability of the composition. This fact was checked in patent application AO 01/97805, which compares the bioavailability of tablets obtained by the considered method and capsules of a similar composition.

However, the authors of the present invention unexpectedly found that a small change in the composition of valsartan-based formulations eliminates the need for compression at all. As a result, not only the labor costs for obtaining the dosage form are reduced, but also an improved tablet disintegration rate is guaranteed, which does not require the search for the optimal pressure.

Description of the invention

The present invention relates to a pharmaceutical composition in the form of tablets containing valsartan, which is an active substance used to treat hypertension, sometimes a combination of ealsartan with hydrochlorothiazide, which is obtained by direct tabletting. Hydrochlorothiazide is a thiazide diuretic with a diuretic and hypotensive effect, and in combination with valsartan, an increase in the hypotensive effect occurs.

The essence of dry tabletting is the preparation of tablets by dry mixing. The tablet material obtained in this way can be used to compress the core and / or tablets without further processing.

The preparation of tablet material is carried out in a technologically simple way; this method is limited only to those technological stages that are not economical in terms of energy and time. The preparation of tablets does not include processes requiring the use of a load, such as the introduction of a humidifier into the mixture of the active substance and additives, as well as dry granulation by compacting the mixture of the active substance and additives in order to obtain tablet material.

The compression of the tablet material obtained by dry mixing, allows to obtain the core and / or tablets with satisfactory parameters, and in addition, the aforementioned method of preparation and selection of additives according to the present invention guarantees good stability of the formulation and the desired physical properties of the dosage form.

The direct tabletting technology is not only simple, but, above all, it is one of the softest of the existing processes. As a result of this, this process demonstrates further progress in comparison with the previously described dry granulation technologies, which are associated with compaction and, therefore, with the need to apply elevated pressures, which subsequently leads to problems associated with the release of the drug into the patient's body. These problems increase the likelihood that a significant portion of the drug is not used at all.

However, to use direct tabletting, it is necessary to find a mixture of the active substance and additives that is capable of undergoing tabletting without any modifications to form tablets that satisfy all the necessary requirements. The pharmaceutical composition in the form of a tablet must be strong enough to withstand various loads during transportation. However, it must be disintegrated quickly enough when interacting with water to release the active substance into the solution before passing through the upper digestive tract of the patient. Values of tablet strength and the possibility of isolation (dissolution) of the active substance are two, to one degree or another, antagonistic factors, and in all cases, the optimal conditions for each case should be chosen.

In the case of direct tabletting technology, additives are selected which have particularly good tabletting properties. These additives primarily include lactose granulate or microcrystalline cellulose. Then, the substance in question, taken in large excess, is mixed with the active substance, as a result of which the positive tabletting properties of such an additive prevail in the mixture. However, such an excess is not used in every case. When using valsartan, the maximum dose of which is 160 mg, the technology under consideration should ensure the production of large, durable, capable of swallowing tablets weighing more than 1 g.

Surprisingly, the patent application AO 97/49394 notes the possibility of producing 300 mg tablets containing 160 mg of valsartan by compression. However, much greater success is achieved when such tablets can be obtained without any granulation.

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Accordingly, a mixture suitable for direct tabletting, or a tablet made by such technology, preferably contains 30-60% valsartan.

The tablet material described in the present invention includes, in addition to the active substance, valsartan, an optional combination of valsartan with hydrochlorothiazide, other additives, the most important of which is an appropriately selected excipient, which decisively affects the quality of the obtained tablets. For direct tabletting, it is necessary to choose a filler with a specific particle size and use it in a certain amount.

It was found that in the case of valsartan, optionally in a mixture with hydrochlorothiazide, it is necessary to select a particle size of the filler in the range of 10-1000 microns, preferably 50-400 microns and to use the filler in an amount of 20-60 wt.%, Preferably 40-60 wt.% .

The filler may be selected from the group consisting of microcrystalline cellulose, lactose, polyhydric alcohols mannitol or sorbitol, calcium hydrogen phosphate secondary, and combinations of microcrystalline cellulose with a mono- or oligosaccharide or polyol.

According to the present invention, a preferred filler composition comprises microcrystalline cellulose with a particle size of 10-1000 microns, preferably 50-190 microns, especially 90 microns, in an amount of 40-60 wt.%, Spray dried anhydrous lactose with a particle size of 10-250 microns, preferably 150 -250 μm, in an amount of 30-60%, pressed lactose hydrate with a particle size of 10-250 μm, in an amount of 40-60 wt.%, A polyhydric alcohol selected from mannitol or sorbitol, which is a pressed (pressed) material with a particle size 100-850 microns, prefer 200-400 microns, in an amount of 40-60 wt.%, calcium acid phosphate with a particle size of 10-200 microns in an amount of 40-60 wt.%, a combination of microcrystalline cellulose with lactose, preferably spray-dried anhydrous lactose in a mass ratio of 1: 2-2: 1 and in an amount of 20-55%, and a combination of microcrystalline cellulose with polyhydric alcohol, preferably extruded (pressed) polyhydric alcohol in a ratio of 1: 2 and in an amount of 20-55% based on the total weight of the formulation.

Microcrystalline cellulose, and optionally a mixture thereof with another filler, is a particularly preferred filler. Using a suitable combination of excipients, combining the advantages of both components, it is possible to obtain a composition from which a tablet of the smallest size is prepared. A preferred combination is a mixture of microcrystalline cellulose with lactose or a polyhydric alcohol such as mannitol.

The composition of the present invention may also contain substances that modify the flow properties of the tablet material, anti-adhesive components that facilitate the tabletting process, as well as components that contribute to the disintegration of the tablets.

In accordance with another embodiment of the invention, the tablet contains 3-10% of a disintegrating component, which is preferably carboxymethyl starch sodium salt. This substance additionally increases the rate of disintegration of the tablet and provides a high rate of release of the active component.

According to another embodiment, the tablet-making mixture comprises substances that improve its flow properties. The most suitable material for the described mixture is colloidal silicon dioxide (KHSA sOIaS apyubsa), preferably used in an amount of 0.1-10 wt.%, Most preferably 0.5-2 wt.%. The presence of such substances is important to prevent fluctuations in tablet mass that occur when the solid mixture does not flow correctly from the hopper into a high-speed tabletting device.

The mixture in question may also contain a release agent, preferably magnesium stearate, in an amount of 0.1-10 wt.%, Preferably 0.5-4 wt.%.

Tablet material or tablets can be prepared from the above mixtures by dry method, using dry mixing and direct tableting.

The tablets obtained in accordance with the present invention, guarantee the reproducibility of the process of their production.

The advantage of preparing tablet material is the low cost of energy and time.

The above-described method for producing valsartan-containing tablet material and solid dosage forms by direct tabletting using dry mixing and the appropriate selection of additives according to the invention allows to obtain tablet material and solid dosage forms with excellent physical parameters.

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Examples Example 1.

Coated tablets containing 160 mg of valsartan

Source materials Weight x * Wa1zagEapit 0.16000 g Microcrystalline cellulose, particle size 90 microns 0.11700 g Sodium Carboxymethyl Starch 0.01600 g Colloidal silicon dioxide 0.00600 g Magnesium stearate 0.00600 g Total core mass in g 0.30500 g ZEIT 3084 Orange 0.00150 g 5erSh1t 3048 yellow 0.01350 g Purified water 0.07000 g Total weight of coated tablet in g: 0.32000 g

Description of the technology for the preparation of tablet material (dry method, direct tabletting).

1. Mixing I: the active substance, microcrystalline cellulose and sodium carboxymethyl starch were mixed in a homogenizer for 15 minutes.

2. Mixing II: final processing — colloidal silicon dioxide and magnesium stearate were added to the homogenizer and the contents were mixed for 15 minutes.

3. The manufacture of tablets.

Two important factors for the tablets obtained in this way were determined: the cracking resistance necessary to preserve the integrity of the tablets during their transportation, and the rate of release of the active substance into the dissolving medium, the value of which determines the availability of the drug for the patient's body. Both characteristics were measured by standard methods.

The resulting tablets had resistance to cracking at least 70n, which guarantees no damage during their normal transportation.

When testing the release rate of the active substance, it was found that at least 75% of the total amount of active substance is released in 45 minutes. The result obtained is in good agreement with the characteristics of the already registered and marketed juwap and yeougiz drugs.

Thus, we can conclude that tablets obtained in a new way, have properties identical to those of products obtained by known standard methods.

Example 2. A filler of microcrystalline cellulose.

Coated tablets containing 40 mg of valsartan

Source materials Mass g Wa1zagCapis 0.040000 g Microcrystalline cellulose, particle size 90 microns 0.048000 g Sodium Carboxymethyl Starch 0.004000 g Colloidal silicon dioxide 0.001500 g Magnesium stearate 0.001500 g Total core mass in g: 0.095000 g

The tablet core was coated according to the method of Example 1.

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Coated tablets containing 80 mg of valsartan

Source materials Mass g Ya 0.080000 g Microcrystalline cellulose, particle size 90 microns 0.096000 g Sodium Carboxymethyl Starch 0.008000 g Colloidal silicon dioxide 0.003000 g Magnesium stearate 0.003000 g The total mass of the core and g: 0.190000 g

The tablet core was coated according to the method of Example 1.

Coated tablets containing 160 mg of valsartan

Source materials Weight x ¹ Wad-zhapapit 0.160000 g Microcrystalline cellulose, particle size 90 microns 0.192000 g Sodium Carboxymethyl Starch 0.016000 g Colloidal silicon dioxide 0.006000 g Magnesium stearate 0.006000 g Total core mass in g: 0.380000 g

The tablet core was coated according to the method of Example 1.

Coated tablets containing 320 mg of valsartan

Source materials Mass, x> Wa1zag £ apigp 0.320000 g Microcrystalline cellulose, particle size 90 microns 0.384000 g Sodium Carboxymethyl Starch 0.0032000 g Colloidal silicon dioxide 0.012000 g Magnesium stearate 0.012000 — g-- Total core mass in g: 0.760000 g

The tablet core was coated according to the method of Example 1.

Description of the technology for the preparation of tablet material (dry method, direct tabletting).

1. Mixing I: the active substance, microcrystalline cellulose and sodium carboxymethyl starch were mixed in a homogenizer for 15 minutes.

2. Mixing II: final processing — colloidal silicon dioxide and magnesium stearate were added to the homogenizer and the contents were mixed for 15 minutes.

3. The manufacture of tablets.

Two important factors for the tablets obtained in this way were determined: the cracking resistance necessary to preserve the integrity of the tablets during their transportation, and the rate of release of the active substance into the dissolving medium, the value of which determines the availability of the drug for the patient's body. Both characteristics were measured by standard methods.

The resulting tablets had a cracking resistance of at least 70n, which guarantees no damage during normal transportation.

When testing the release rate of the active substance, it was found that at least 75% of the total amount of active substance is released in 45 minutes. The result obtained is in good agreement with the characteristics of the already registered and marketed drugs Buuap and ΧοναΠίδ.

Thus, we can conclude that tablets obtained in a new way, have properties identical to the properties of products prepared by known standard methods.

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Example 3. The combination of microcrystalline cellulose and mannitol.

Coated tablets containing 80 mg of valsartan

Source materials Mass g Baaaaaaaaaaaaaaaaa 0.080000 g Microcrystalline cellulose, particle size 90 microns 0.032000 g Mannitol (Reag1I: o1 400 CS), particle size 360 microns 0.064000 g Sodium carboxymethyl starch 0.008000 g Colloidal silicon dioxide 0.003000 g Magnesium stearate 0.003000 g Total core mass in g: 0.190000 g

The tablets were prepared according to the method of example 2. The core of the tablet was coated according to the method of example 1.

Example 4. The combination of microcrystalline cellulose and anhydrous lactose.

Coated tablets containing 80 mg of valsartan

Source materials Mass g WaZagTapit 0.080000 g Microcrystalline cellulose, particle size 90 microns 0.049000 g Anhydrous lactose AXIS 21, particle size 250 μm 0.047000 g Sodium carboxymethyl starch 0.008000 g Colloidal silicon dioxide 0.003000 g Magnesium stearate 0.003000 Ϊ Total core mass in g: 0.190000 g

The processing was carried out according to the method of example 2. The tablet core was coated according to the method of example 1.

Example 5

Mannitol was used as a filler.

Coated tablets containing 80 mg of valsartan

Source materials Mass g Wad ZagEapit 0.080000 g Mannitol (Reag11-L0 400 CC), 360 micron 0.096000 g Sodium carboxymethyl starch 0.008000 g Colloidal silicon dioxide 0.003000 g Magnesium stearate 0.003000 g Total core mass in g: 0.190000 g

The tablets were coated according to the procedure of Example 1. Example 6. A composition containing less than 35% valsartan.

Coated tablets containing 160 mg valsa ethane Source materials Mass g Wazagbapit 0.160000 g Microcrystalline cellulose, particle size 90 microns 0.282000 g Sodium carboxymethyl starch 0.016000 g Colloidal Silicon Dicoside 0.006000 g Magnesium stearate 0.006000 g Total core mass in g 0.470000 g ZERGEIT 3048 yellow 0.013500 g ZER1PC 3084 orange 0.001500 g Total weight of the coated tablet in x>: 0.485000 g

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Claims (10)

CLAIM 1. Pharmaceutical composition containing valsartan, possibly in the form of a combination of valsartan with hydrochlorothiazide, obtained by direct tableting, characterized in that it contains a filler with a particle size of 100-1000 μm, preferably 50-400 μm, in an amount of 20-60, preferably 40-60 wt.% calculated on the total weight of the formulation. 2. The pharmaceutical composition according to claim 1, characterized in that it contains a filler selected from the group comprising microcrystalline cellulose, lactose, a polyhydric alcohol, which is a mannitol or sorbitol, secondary calcium phosphate, and a combination of microcrystalline cellulose with a mono- or oligosaccharide or polyhydric alcohol. 3. The pharmaceutical composition according to claim 2, characterized in that it contains 30-60 wt.% Valsartan, optionally 3-12 wt.% Hydrochlorotriazide and a filler selected from the group including microcrystalline cellulose with a particle size of 10-1000 μm, preferably 50 -190 microns, in the amount of 40-60 wt.%, Spray-dried anhydrous lactose with a particle size of 10-250 microns in the amount of 30-60 wt.%, Lactose hydrate with a particle size of 10-200 microns in the amount of 40-60 wt.% polyhydric alcohol selected from mannitol or sorbitol, which is a pressed material with a particle size eggs 100-850 microns in the amount of 40-60 wt.%, secondary acidic calcium phosphate with a particle size of 10200 microns in the amount of 40-60 wt.%, a combination of microcrystalline cellulose with lactose, preferably spray-dried lactose, in a mass ratio of 1: 2- 2: 1, taken in an amount of 2055 wt.% And a combination of microcrystalline cellulose and a polyhydric alcohol, preferably a molded polyhydric alcohol, in a 1: 2 ratio and in an amount of 20-55 wt.% Calculated on the total weight of the formulation. 4. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that it further includes a disintegrant, a substance that alters the flow properties of the tablet material and a release agent. 5. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that it comprises 3-10 wt.% Disintegrating component, preferably the carboxymethyl starch sodium salt. 6. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that it comprises 0.1 to 10 wt.%, Preferably 0.5 to 2 wt.% Modifier flow properties of the tablet material, preferably representing colloidal silicon dioxide. 7. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that it comprises 0.1-10 wt.%, Preferably 0.5-4 wt.% Antiadhesive, preferably representing magnesium stearate. 8. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that it comprises 160 mg of valsartan, 8-200 mg of excipient and 10-20 mg of sodium carboxymethyl starch. 9. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that it comprises 80 mg of valsartan, 40-100 mg of excipient and 5-10 mg of sodium carboxymethyl starch. 10. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that it includes 40 mg of valsartan, 20-50 mg of excipient and 2.5-5 mg of sodium carboxymethyl starch.