Multi-layered tablet, containing effervescent layer

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the pharmaceutical industry and provides a multilayered tablet, containing an effervescent layer, containing hydrochlorothiazide or amlodipine or its salt as an active ingredient, carbonate salt and organic acid, and a telmisartan-containing layer.

EFFECT: obtaining the multilayered tablet, containing the effervescent layer.

1 dwg, 9 tbl, 9 ex

 

Area of technology

[1] the Present invention relates to a multilayer tablet containing: effervescently (providing a rapid release of gases-note. translation.) the layer containing the gidrohlortiazid or amlodipine or its salt; and a layer containing telmisartan.

Prior art

[2] In the treatment of hypertension are different antihypertensive agents such as diuretics, beta-blockers, alpha-blockers, calcium channel blockers, vasodilator agents, as well as receptor antagonists angiotensin. In addition to this is the development of pharmaceutical compositions, simultaneously containing antihypertensive agents with different pharmacological mechanisms, with the aim of obtaining a better treatment effects. For example, it was reported pharmaceutical compositions containing a combination of receptor antagonist of angiotensin and diuretic; or a receptor antagonist of angiotensin and calcium channel blocker. One of the most important factors to be considered in the development of the pharmaceutical combination compositions, is that the appropriate medicines included in the compositions should exhibit biological properties similar to the composition shown with one drug.

[3] as a prior art for �of readline differences in the release characteristics between the water-insoluble telmisartan and a diuretic or a calcium channel blocker in WO 2003/059327 and WO 2006/048208 disclosed bilayer tablets bilayer tablets. In WO 2003/059327 was disclosed two-layer pharmaceutical tablet containing a first layer containing telmisartan in more than 90% of the amorphous form into the soluble matrix tablets and the second layer containing gidrohlortiazid in the collapsing matrix tablets. In addition, in WO 2006/048208 was disclosed pharmaceutical tablet containing a first layer of telmisartan in a dissolving matrix tablets, and the second layer of amlodipine at the same time blur the matrix tablets. Tablet disclosed in WO 2003/059327 and WO 2006/048208, are double-layer, each of which has a first layer formulated for immediate release of telmisartan; and a second layer formulated for immediate release of hydrochlorothiazide or amlodipine from bystrorasshiryayuscheysya of a matrix tablet by means of the destruction as a result of swelling.

[4] Although a two-layer tablet disclosed in WO 2003/059327 and WO 2006/048208, formulated to be immediate release of each component, they are still unsatisfactory in terms of minimising deviations of the nature of dissolution in accordance with the surrounding conditions such as pH changes in the gastrointestinal tract or alteration of gastrointestinal motility (e.g., reduced gastrointestinal motility). That is, in the case of destruction of the matrix tablets in which visual�to approve medicines as diuretics or calcium channel blockers is due to the swelling and erosion, the nature of their dissolution is influenced by the rotational speed blade mixer, which indicates that the absorption of the drug may vary depending on gastrointestinal motility of the patient.

Disclosure of the invention

Technical problem

[5] the Authors present invention have been conducted various studies to develop a pharmaceutical combination composition comprising telmisartan with gidrohlortiazidom or amlodipine or its salt and having an immediate drug release without the influence of surrounding conditions. As a result, it was found that multilayer tablet having effervescently layer containing gidrohlortiazid or amlodipine or its salt, carbonate salt and an organic acid, rapidly releases the drug by immediate rapid discharge of gaseous CO2in the gastrointestinal tract, thereby showing homogeneous dissolution without affecting gastrointestinal motility of the patient.

[6] in addition, it was also found that when telesecundarias layer is formed by preparing telmisartan by granulation in a fluidized bed using a granulator fluidized bed, usually used in the pharmaceutical industry instead of a spray dryer, not�Ko allows you to achieve excellent characteristics of dissolution of telmisartan, but also the specified layer can be formed with high yield, thus suggesting a high efficiency of the process.

[7] Accordingly, the present invention obespecivaet multilayer tablet containing: effervescently layer containing gidrohlortiazid or amlodipine or its salt; and telesecundarias layer.

The solution of the problem

[8] In accordance with an aspect of the present invention provides a multilayer tablet containing: effervescently layer containing gidrohlortiazid or amlodipine or its salt as an active ingredient, a carbonate salt and an organic acid; and telesecundarias layer.

[9] According to one embodiment of the present invention provides a multilayer tablet in which the active ingredient effervescent layer is gidrohlortiazidom and in which during the test "dissolution" method blade mixer without its rotation at a pH of 1.2 dissolved amount of hydrochlorothiazide during the first 15 minutes is 50 wt.% or more of the total weight of hydrochlorothiazide.

[10] According to another exemplary embodiment of the present invention provides a multilayer tablet in which the active ingredient effervescent layer is amlodipine or its salt and in which during the test "dissolution" �etodo blade mixer without its rotation at a pH of 1.2 dissolved amount of amlodipine or its salt during the first 15 minutes is 50 wt.% or more of the total weight of amlodipine or its salt. Salt of amlodipine could be the amlodipine malate, the amlodipine besylate, amlodipine by mesilato or amlodipine camsylate.

[11] In the multilayer tablet of the present invention the carbonate salt may be selected from the group consisting of sodium bicarbonate, potassium carbonate, sodium carbonate, calcium carbonate, ammonium carbonate, magnesium carbonate and mixtures thereof; and organic acid may be selected from the group consisting of ascorbic acid, succinic acid, tartaric acid, citric acid, malic acid, fumaric acid and mixtures thereof.

Advantageous effects of invention

[12] multi-Layered tablet in accordance with the present invention includes effervescently layer containing gidrohlortiazid or amlodipine or its salt that provides a rapid release of the drug through the immediate rapid discharge of generated gas CO2in the gastro-intestinal tract. Thus, the multilayer tablet of the present invention allows to minimize the deviations of the nature of the dissolution of the active ingredient even in elderly patients with reduced motility of the gastrointestinal tract. That is, it can be expected that multi-layered tablet of the present invention exhibits a uniform release of the drug through �of Nigeria any effects, due to changes in the environment in the gastro-intestinal tract caused by various complications, the age and condition of patients, etc. in Addition, since telesecundarias layer of the multilayer tablet of the present invention is formed by preparing telmisartan by granulation in a fluidized bed, it is possible to expect high performance along with excellent dissolution characteristics of telmisartan.

Brief description of the drawings

[13] In Fig.1 presents the results of the test "dissolution" of telmisartan in tablets manufactured according to the present invention (examples 2.4 to 1 and 7), and the tablets of comparative example in a buffer solution having a pH of 1.2.

The best example of carrying out the invention

[14] the Present invention provides a multilayer tablet containing: effervescently layer containing gidrohlortiazid or amlodipine or its salt as an active ingredient, a carbonate salt and an organic acid; and telesecundarias layer.

[15] multi-Layered tablet in accordance with the present invention, including effervescently layer containing gidrohlortiazid or amlodipine or its salt, quickly rapidly allocates the resulting gas CO2in the gastrointestinal tract to release the drug. Thus, many�Loen tablet in accordance with the present invention allows to minimize the deviations of the nature of the dissolution of the active ingredient even in elderly patients with reduced motility of the gastrointestinal tract. That is, when effervescently layer in contact with water, it immediately rapidly generate gas, resulting in the formation of micro-cavities in it. Through these micro-cavities in the active ingredient dissolves quickly. Namely, 50% or more of hydrochlorothiazide or amlodipine quick dissolve within 15 minutes even in the absence of mixing. This rapid dissolution surprising, considering the usual formulations, ensuring the release of 20% or less of the drug even after 120 minutes in the absence of mixing.

[16] gidrohlortiazid (chemical name:

6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-sulfonamide-1,1-dioxide) is a diuretic used to treat edema and hypertension and is generally assigned to oral. In a multilayer tablet according to the present invention can be used the proper amount of hydrochlorothiazide on the basis of his a therapeutically effective amount. For example, the amount of hydrochlorothiazide may be in the range of 5 to 50 mg in one tablet.

[17] Amlodipine is a calcium channel blocker and has the chemical name:

3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate). Salt of amlodipine may be a malate, besylate, mesylates or ka�the Silat, preferably the besylate. In a multilayer tablet according to the present invention can be used the proper amount of amlodipine or its salt based on its therapeutically effective amount. For example, the amount of amlodipine or its salt may be in the range of 1 to 20 mg (as amlodipine) in one pill.

[18] Effervescently layer can be fabricated by (a) formation of granules comprising gidrohlortiazid or amlodipine or its salt as an active ingredient and a carbonate salt, (b) mixing the organic acid with them and (c) pressing the resulting mixture. Alternatively effervescently layer can be fabricated by (a') the formation of granules comprising an active ingredient and an organic acid, (b') mixing the carbonate salt with them, and (c') pressing the resulting mixture.

[19] the Granules can be manufactured by spraying binder solution in the process of fluidization of the mixture of hydrochlorothiazide or amlodipine or its salt, a diluent, a carbonate salt or an organic acid in the granulator fluidized bed. The binder solution can be obtained by dissolving at least one binder selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, hydroxypropylmethylcellulose and polyviny�marketing of alcohol in water, alcohol, or mixtures thereof. Thus, the resulting granules may further comprise at least one binder selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, hydroxypropylmethylcellulose and polyvinyl alcohol.

[20] the diluent may be any diluent commonly used in the pharmaceutical field. Examples of the diluent include glucose, fructose, lactose, sucrose, sorbitol, mannitol, maltol, isomalt, xylitol, and a combination thereof. Preferably rabavilas can be isomalt, lactose or a mixture thereof. The amount of diluent may be in the range from 40 to 80 wt.% the total mass effervescent layer, but is not limited to them.

[21] the Carbonate salt may be any carbonate salt which reacts with the organic acid in the human body to form a gas of CO2. For example, the carbonate salt may be at least one selected from the group consisting of sodium bicarbonate, potassium carbonate, sodium carbonate, calcium carbonate, ammonium carbonate and magnesium carbonate; preferably sodium bicarbonate. In addition, the organic acid may be at least one selected from the group consisting of ascorbic acid, succinic acid, tartaric acid, citric acid, malic acid and fumaric acid; preferably lemon sour�s. The amount of carbonate salt may be in the range from 0.5 to 30 wt.%, preferably from 1 to 20 wt.%, more preferably from 1 to 15 wt.% the total mass effervescent layer. The amount of organic acid may be in the range of 1 to 30 wt.%, preferably from 1 to 15 wt.% the total mass effervescent layer.

[22] in Addition to the active ingredient (hydrochlorothiazide or amlodipine or its salt), a diluent, carbonate salts and organic acids effervescently layer may also contain pharmaceutically acceptable conventional additives, such as a moving substance, such as magnesium stearate or sodium fumarate.

[23] in addition, by using the present invention it was found that the granules obtained by granulation in a fluidized bed (i.e., the pellets made by spraying on sugar telesecundarias solution obtained by dissolving telmisartan together with meglumine and sodium hydroxide in an organic solvent), have excellent dissolution characteristics. In addition, because telesecundarias layer can be formed with high yield by granulation in a fluidized bed, there is a high efficiency of the process.

[24] the Organic solvent may be anhydrous ethanol or a mixed solvent of anhydrous ethanol� and methylene chloride. In a mixed solvent of anhydrous ethanol and methylene chloride, the weight ratio of anhydrous ethanol and methylene chloride may be 1:2 to 7, preferably 1:3-5, more preferably about 1:3. Examples of sugars include sorbitol, mannitol, isomalt, etc. if necessary telesecundarias solution can optionally include a binder, such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose and polyvinyl alcohol. In telesecundarias layer can be used the proper amount of telmisartan on the basis of its therapeutically effective amounts, e.g. in the range from 20 to 160 mg per one tablet (e.g., bi-layer tablet). In addition, the number of individually meglumine and sodium hydroxide may be in the range from 0.5 to 10 wt.%, but is not limited to this.

[25] According to the exemplary embodiment of the present invention provides a multilayer tablet in which the active ingredient effervescent layer is gidrohlortiazidom and in which, when the test "dissolution" was performed by the method of a blade stirrer at a pH of 1.2 without rotating blade mixer, the dissolved amount of hydrochlorothiazide during the first 15 minutes is 50 wt.% or more of the total weight of hydrochlorothiazide. According to another exemplary embodiment of the present invention �provides a multilayer tablet, in which the active ingredient effervescent layer is amlodipine or its salt and in which when the test "dissolution" was performed by the method of a blade stirrer at a pH of 1.2 without rotating blade mixer, the dissolved amount of amlodipine or its salt during the first 15 minutes is 50 wt.% or more of the total weight of amlodipine or its salt. Salt of amlodipine could be the amlodipine malate, the amlodipine besylate, amlodipine by mesilato or amlodipine camsylate.

[26] In addition to effervescent layer and telesecundarias layer of the multilayer tablet of the present invention may further comprise non-drug layer containing commonly available excipients in the pharmaceutical field, as a separate layer (for example, it may be a three-layer tablet form). Examples of auxiliary substances may include sugar or cellulose derivatives, such as lactose, microcrystalline cellulose, isomalt, etc.

[27] the Multilayer tablet of the present invention is manufactured using a conventional method of preparation of multilayered tablets. For example, in the manufacture of multilayer tablets bilayer tablets of a mixture of organic acid and granules containing gidrohlortiazid or amlodipine or its salt and a carbonate salt or a mixture �arbonate salt and granules, containing gidrohlortiazid or amlodipine or its salt and an organic acid, pressed together with a moving substance, such as magnesium stearate, to form effervescent layer. And then may be implemented compressing granules containing telmisartan, or a mixture of granules containing telmisartan, and pharmaceutically acceptable excipients (e.g., diluents or moving substances) for the formation of a separate layer.

[28] Hereinafter the present invention will be described in more detail with reference to the following examples. These examples are given solely for demonstrative purposes and are not intended to limit the scope of the invention.

[29]

[30] Example 1

[31] 8,00 kg telmisartan, 8,00 kg polyvinylpyrrolidone, 2,40 kg meglumine and 0.67 kg of sodium hydroxide was dissolved in 106,00 kg of anhydrous ethanol. Granulation was performed by spraying the solution in the process of fluidization 14,40 kg of sorbitol in the granulator fluidized bed. The temperature at the inlet and outlet temperature of the granulator fluidized bed was 60°C and 40°C respectively, the spraying speed was g 100,00 per minute. By means of the method described above produced three batches. Each party made a selection of pellets from its upper, middle and lower parts to measure the amount contained in each of the parts of telmisartan for�the teachings of his interest (%) content by weight relative to theoretically calculated quantity. And in each batch measured the total quantity of products in comparison with full size download the to compute the output. The results are presented in tables 1 and 2.

[32] table 1

[Table 1]

[Table]
Telmisartan granules (wt.%)
Party 1Party 2Party 3
The upper part98,66101,28100,09
The middle part101,89play responsibly 99.3799,55
The lower part98,9199,7499,99
The average value99,82100,13of 99.88

[33]

[34] table 2

[Table 2]

[Table]
The output of each batch (wt.%)
Party 1Party 2Party 3
Full size download33,4733,4733,47
Detailed product quantity33,4033,2033,32
Yield (wt.%)by 99.7999,1999,55

[35] Referring to table 1 and table 2, it can be seen that by granulation granulation in a fluidized bed it is possible to produce granules containing telmisartan, with high production efficiency, while ensuring uniformity and no loss of contents.

[36]

[37] Example 2. Manufacture of tablets containing gidrohlortiazid and telmisartan

[38] 0,80 kg of polyvinylpyrrolidone was completely dissolved in 10,00 kg of ethanol to obtain a binder solution. Granulation was performed by spraying the binder solution in the amount of 60,00 g per minute by the fluidization of a mixture of 1.25 kg of hydrochlorothiazide, 7,10 kg isomaltol, 7,75 kg of anhydrous lactose and 1.80 kg of sodium bicarbonate in the granulator fluidized bed. The temperature at the inlet and outlet temperature of the pellet mill to�pasim layer was 50°C and 30°C respectively. 18,70 kg of the obtained pellets were mixed with 1.00 kg of citric acid and 0.30 kg of magnesium stearate to obtain a mixture (mixture A).

[39] 8,00 kg telmisartan, 8,00 kg polyvinylpyrrolidone, 2,40 kg meglumine and 0.67 kg of sodium hydroxide was dissolved in 106,00 kg of anhydrous ethanol. Granulation was performed by spraying the solution in the process of fluidization 14,40 kg of sorbitol in the granulator fluidized bed. The temperature at the inlet and outlet temperature of the granulator fluidized bed was 60°C and 40°C respectively, the rate of sputtering was $ 100,00 g per minute. 33,47 kg of the obtained pellets, 14,02 kg of sorbitol and 0.51 kg of magnesium stearate were mixed to obtain Telesecundaria mixture (mixture B).

[40] a Mixture of A and B is pressed by the compressor for double-layer tablets (manufacturer: Gisan Machine Inc., model name: rotary tablet press press SPT/TP500/41) for the manufacture of bilayer tablets. The obtained two-layer tablet contain 12,50 mg of hydrochlorothiazide and 80,00 mg telmisartan each.

[41]

[42] Example 3. Manufacture of tablets containing gidrohlortiazid and telmisartan.

[43] 0,80 kg of polyvinylpyrrolidone was completely dissolved in 10,00 kg of ethanol to obtain a binder solution. Granulation was performed by spraying the binder solution with a flow rate of 60,00 g per minute in the process of fluidization of a mixture of 1.25 kg of hydrochlorothiazide, 7,10 kg isomalt, 7,75 kg �Espagnol lactose and 1.00 kg of citric acid in the pellet mill kipas layer. The temperature at the inlet and outlet temperature of the granulator fluidized bed at 50°C and 30°C respectively. 17,90 kg of the obtained pellets were mixed with 1,80 kg of sodium bicarbonate and 0.30 kg of magnesium stearate to obtain a mixture (mixture A').

[44] the Compound A' and compound B (prepared in the same manner as in example 2) was pressed with a compressor for double-layer tablets (manufacturer: Gisan Machine Inc., model name: rotary tablet press press SPT/TP500/41) for the manufacture of bilayer tablets. The obtained two-layer tablet contain 12,50 mg of hydrochlorothiazide and 80,00 mg telmisartan each.

[45]

[46] Example 4. Manufacture of tablets containing gidrohlortiazid and telmisartan.

[47] Using a mixture containing gidrohlortiazid (mixture A) and mixture containing telmisartan (mixture B), which were obtained in the same manner as in example 2 produced a three-layer tablet as described in table 3. Table 3 shows the mass of each component in one pill. That is, using a mixture, forming the first layer containing 12,50 mg of hydrochlorothiazide, using mixed powders obtained by mixing lactose, microcrystalline cellulose or isomalt with 0.50% magnesium stearate (corresponding powders are presented in table 3 as "lactose blend", "blend with microcrystalline cellulose" and "isomaltulose mixture"),formed the second layer. And then for making a three-layer tablet formed a third layer containing 80,00 mg of telmisartan using a mixture of B.

[48] table 3

[Table 3]

[Table]
Three-layer tablet
Example 4-1Example 4-2Example 4-3
ComponentQty (mg)ComponentQty (mg)ComponentQty (mg)
The first layerMix A200Mix A200Mix A200
The second layerLactose mixture150A mixture with microcrystalline cellulose150Isomaltulose mixture150
�rety layer Mixture B480Mixture B480Mixture B480
Total weight830 mg830 mg830 mg

[49]

[50] Example 5. Manufacture of tablets containing amlodipine besylate and telmisartan.

[51] 0,80 kg of polyvinylpyrrolidone was completely dissolved in 10,00 kg of ethanol to obtain a binder solution. Granulation was performed by spraying the binder solution with a flow rate of 60,00 g per minute in the process of fluidization of a mixture of 0.69 kg of amlodipine besylate, 7,00 kg isomalt, 8,32 kg of anhydrous lactose and 1.80 kg of sodium bicarbonate in the granulator fluidized bed. The temperature at the inlet and outlet temperature of the granulator fluidized bed was 50°C and 30°C respectively. 18,61 kg of the obtained pellets were mixed with 1.00 kg of citric acid and 0.30 kg of magnesium stearate to obtain a mixture (mixture C).

[52] the Mixture C and mixture B (obtained in the same manner as in example 2) was pressed with a compressor for double-layer tablets (manufacturer: Gisan Machine Inc., model name: rotary tablet press press SPT/TP500/41) for the manufacture of bilayer tablets. The resulting Duhs�eunie tablets contain 5,00 mg of amlodipine and 80,00 mg telmisartan each.

[53]

[54] Example 6. Manufacture of tablets containing amlodipine besylate and telmisartan.

[55] 0,80 kg of polyvinylpyrrolidone was completely dissolved in 10,00 kg of ethanol to obtain a binder solution. Granulation was performed by spraying the binder solution with a flow rate of 60,00 g per minute in the process of fluidization of a mixture of 0.69 kg of amlodipine besylate, 7,00 kg isomalt, 8,32 kg of anhydrous lactose and 1.00 kg of citric acid in the granulator fluidized bed. The temperature at the inlet and outlet temperature of the granulator fluidized bed was 50°C and 30°C respectively. 17,81 kg of the obtained pellets were mixed with 1,80 kg of sodium bicarbonate and 0.30 kg of magnesium stearate to obtain a mixture (mixture C).

[56] Compound C and compound B (obtained in the same manner as in example 2) was pressed with a compressor for double-layer tablets (manufacturer: Gisan Machine Inc., model name: rotary tablet press press SPT/TP500/41) for the manufacture of bilayer tablets. The obtained two-layer tablet contain 5,00 mg of amlodipine and 80,00 mg telmisartan each.

[57]

[58] Example 7. Manufacture of tablets containing gidrohlortiazid and telmisartan.

[59] 240,00 g of telmisartan, 72,00 g polyvinylpyrrolidone, 72,00 g meglumine and 20,16 g of sodium hydroxide was completely dissolved in 3200,00 g of anhydrous ethanol. Granulation was performed by spraying the solution in the course of pseudology�t 600,00 g of isomalt in the granulator fluidized bed. The temperature at the inlet and outlet temperature of the granulator fluidized bed was 60°C and 40°C respectively, the spray rate was 6 g per minute. 334,72 g of the granules, 140,27 g isomalt and 5.01 g of magnesium stearate were mixed to obtain Telesecundaria mixture.

[60] Using telesecundarias mixture and hydrochlorothiazidebuy the mixture obtained in the same manner as in example 2 (i.e., a mixture), produced a two-layer tablet in the same manner as in example 2. The obtained two-layer tablet contains 12.5 mg of hydrochlorothiazide and 80,00 mg telmisartan each.

[61]

[62] Experimental example

[63] the Test "dissolution" and analytical methods are as follows.

[64] (1) the Test "dissolution"

[65] the Test "dissolution" carried out with the use of 900 ml of buffer solution having a pH of 1.2 (solution 1 for the test to destruction in the "General test methods" of the Korean Pharmacopoeia 9th edition), as a solution, which was carried out by dissolving, at a temperature of 37°C in accordance with method II of the test "dissolution" method (paddle stirrer) in the "General methods of analysis" of the Korean Pharmacopoeia 9th edition. After 15 minutes took 5 ml solution, which was carried out by dissolving, for each sample and filtered through a membrane filter with a pore size of 0.45 μm.The filtrate obtained was used to measure the extent of dissolution.

[66]

[67] (2-1) an Analytical method to hydrochlorothiazide or telmisartan

[68] Column: ACQUITY UPLC®VEINS C18, particle size 1.7 μm, length 2.1 m, an internal diameter of 50 mm

[69] - Mobile phase

[70] A: a solution prepared by adding phosphoric acid to the

1000 ml of 0.05 mol/l solution of potassium dihydrogen phosphate to achieve its acidity pH 3.0.

[71] B: acetonitrile

[72] table 4

[Table 4]

[Table]
Time (min)Flow rate (ml/min)Mobile phase A (%)Mobile phase B (%)
00,48020
0,80,48020
1,00,46337
3,50,46337
4,00,48020
5, 0,48020

[73] Detector: UV spectrophotometer (271 nm)

[74] - column Temperature: 40°C

[75]

[76] (2-2) the Analytical method for amlodipine

[77] Column: ACQUITY UPLC®VEINS C18, particle size 1.7 μm, length 2.1 m, inner diameter 100 mm

[78] - Mobile phase: a mixed solution of methanol and 0.03 mol/l solution of potassium dihydrogen phosphate (60:40)

[79] - Flow rate: 0.35 ml/min

[80] Detector: UV spectrophotometer (237 nm)

[81] - column Temperature: 40°C

[82]

[83] Experimental example 1. The test "dissolution" of tablets containing gidrohlortiazid and telmisartan.

[84] the Test "dissolution" held on the tablets obtained in accordance with examples 2 and 3 (tablets containing 12.5 mg of hydrochlorothiazide and 80 mg of telmisartan). The test "dissolution" also conducted using commercially available tablets Micardis plus™ as a comparative example. The test "dissolution" carried out on 6 tablets in each case. To determine the effect, respectively, the speed of stirring blade of the stirrer, the rotation speed of the paddle stirrer was set to 0, 25 and 50 rpm, and for each tablet measured the dissolution rate of respectively the speed of rotation. When the rotational speed of 0 rpm, the degree of dissolution was measured after 15,30,45, 60, 90 and 120 mine�. The degree of dissolution (%) of hydrochlorothiazide, respectively the speed of rotation of a blade stirrer shown in table 5 and table 6.

[85] table 5

[Table 5]

[Table]
The degree of dissolution of hydrochlorothiazide respectively the speed of rotation of a blade stirrer (pH 1, 2, 15 min)
Rotation speed (rpm)TabletThe degree of dissolution (%)
50Example 2to 100.6±2,1
Example 396,5±1,7
Comparative example94,5±0,7
25Example 292,7±1,5
Example 3to 91.1±2,8
Comparative example50,2±11,7
0Example 279,9±7,0
Example 375,1±11,8
Compare�comparative example 4,6±2,6

[86]

[87] table 6

[Table 6]

[Table]
The degree of dissolution of hydrochlorothiazide at a speed of rotation of a blade stirrer 0 rpm (pH 1,2).
15 min30 min45 min60 min90 min120 min
Example 279,9±7,084,0±9,484,6±8,385,2±7,686,4±7,787,5±7,3
Comparative example4,6±2,67,9±5,58,5±3,910,1±4,513,2±5,415,4±5,9

[88] Referring to table 5, it can be seen that the tablets of the present invention show a dilution ratio of 50 wt.% or more within 15 minutes regardless of the speed of rotation. In particular, as shown in table 6, the tablets of comparative example show the extent of RAS�met through 20% or less even after 2 hours, while the tablets of the present invention showing the dissolution rate of 50% or more within 15 minutes. Thus, it can be expected that the immediate drug release can be expected regardless of the environment, especially in elderly patients with reduced motility of the gastrointestinal tract.

[89]

[90] Experimental example 2. The test "dissolution" of tablets containing amlodipine besylate and telmisartan

[91] the Test "dissolution" held on the tablets manufactured in accordance with examples 5 and 6 (pills containing 5.00 mg of amlodipine and 80 mg of telmisartan). The test "dissolution" also conducted using commercially available tablets Norvasc™ 5 mg (Pfizer Inc.) as a comparative example. The test "dissolution" carried out on 6 tablets in each case. To determine the effect, respectively, the speed of stirring blade of the stirrer, the rotation speed blade mixer set at 0 and 50 rpm, and for each tablet measured the dissolution rate of respectively the speed of rotation. The solubility of each tablet was determined at each of these speeds. The degree of dissolution of amlodipine besylate respectively the speed of rotation of paddle stirrers are shown in table 7 and table 8.

[92] table 7]

[Table 7]

[Table]
The degree of dissolution of amlodipine besylate at 50 rpm (pH 1,2)
The degree of dissolution (%)
Example 588,5±5,2
Example 682,5±3,7
Comparative example85,6±4,1

[93]

[94] table 8

[Table 8]

[Table]
The degree of dissolution of amlodipine besylate at 0 rpm (pH 1,2)
The degree of dissolution (%)
Example 562,9±6
Example 658,5±2,5
Comparative example2,1±1,3

[95]

[96] Referring to tables 7 and 8, it can be seen that a two-layer tablet of the present invention have a dissolution rate of 50% or more within 15 minutes. In particular, when the rotation speed of the paddle stirrer 0 rpm dissolution rate of a two-layer tab�etock of the present invention was significantly higher extent of dissolution of the tablets of comparative example.

[97]

[98] Experimental example 3. The test "dissolution" of three-layered tablets containing gidrohlortiazid and telmisartan.

[99] the Test "dissolution" held on the tablets manufactured in accordance with example 4 (tablets containing 12.5 mg of hydrochlorothiazide and 80 mg of telmisartan). The test "dissolution" carried out on 6 tablets in each case. To determine the effect, respectively, the speed of stirring blade of the stirrer, the rotation speed blade mixer set at 0 and 50 rpm, and for each tablet measured the dissolution rate of respectively the speed of rotation. The degree of dissolution (%) of hydrochlorothiazide, respectively the speed of rotation of a blade stirrer shown in table 9.

[100]

Table 9

[Table 9]

Example 4-3
[Table]
The degree of dissolution of hydrochlorothiazide respectively the speed of rotation of a blade stirrer
Rotation speed (rpm)PillsThe degree of dissolution (%)
50Example 4-195,3±2,8
Example 4-298,5±3,1
96,9±2,2
0Example 4-168,7±5,7
Example 4-264,5±7,8
Example 4-3to 66.3±2,2

[101]

[102] Experimental example 4. The test "dissolution" of tablets containing gidrohlortiazid and telmisartan.

[103] the Test "dissolution" held on the tablets manufactured in accordance with example 2.4 to 1 and 7. The test "dissolution" also conducted using commercially available tablets Micardis plus™ as a comparative example. The test "dissolution" held on 3 tablets in each case, when the rotation speed of the paddle stirrer 50 rpm For the test "dissolution" of telmisartan selected 5 ml solution, which was carried out by dissolving, in 15, 30,45, 60, 90 and 120 minutes after the start of the experiment, and then filtered through a membrane filter with a pore size of 0.45 μm. The filtrate obtained was used to determine the degree of dissolution of telmisartan. The results of the test "dissolution" shown in Fig.1. Referring to Fig.1, it can be seen that the tablets of the present invention have a dissolution profile of telmisartan, which has equal or better dissolution profile tell�Sartana in the comparative example.

Multilayer tablet containing:
effervescently layer containing gidrohlortiazid as the active ingredient, sodium bicarbonate and citric acid; and
telesecundarias layer comprising telmisartan as the active ingredient; meglumine; sodium hydroxide; sugar selected from the group consisting of: sorbitol, mannitol and isomalt; and a binder selected from the group consisting of: polyvinylpyrrolidone, hydroxypropylmethylcellulose and polyvinyl alcohol,
with the dissolution of hydrochlorothiazide method blade mixer without its rotation at pH 1.2 in the first 15 minutes is 50 wt.% or more.



 

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13 cl, 9 ex

FIELD: medicine.

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21 cl, 12 ex

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63 cl, 15 dwg, 2 tbl, 29 ex

FIELD: medicine; chemical and pharmaceutical industry.

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14 cl, 1 dwg, 6 tbl, 4 ex

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25 cl, 1 ex

FIELD: medicine, pharmacy.

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8 cl, 6 tbl, 3 dwg, 16 ex

FIELD: medicine, psychiatry, pharmacy.

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5 cl, 1 tbl, 2 ex

FIELD: medicine, chemical-pharmaceutical industry.

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11 cl, 20 tbl, 3 ex, 13 dwg

FIELD: medicine, pharmaceutics.

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79 cl, 10 ex

FIELD: medicine, pharmaceutics.

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18 cl, 14 dwg, 7 tbl, 9 ex

FIELD: chemistry.

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1 ex

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7 cl, 2 dwg, 3 tbl, 14 ex

FIELD: medicine.

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EFFECT: implementing the above application.

6 cl, 7 tbl, 4 ex

FIELD: medicine, pharmaceutics.

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5 cl, 3 dwg, 1 tbl, 1 ex

FIELD: medicine.

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2 cl, 1 ex, 1 tbl

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10 cl, 4 ex, 1 tbl

FIELD: medicine.

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EFFECT: simple process of producing microcapsules of a preparation in water-soluble polymers, high mass output.

3 ex

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