KR101817714B1 - Oral solid composite comprising valsartan - Google Patents

Abstract

The present invention relates to valsartan single- and complex solid preparations, particularly to valsartan having a bulk density of 0.28 to 0.35, wherein the valsartan has a particle size distribution of 1 to 20 mu m particles of 40 to 60% To 60% to 40% of particles, and a process for producing the same.
According to the present invention, by optimizing the bulk density and the particle distribution of valsartan to a predetermined range, valsartan single and complex solid preparations prepared by dry granulation or wet granulation can be used as a solid preparation It is possible to produce a solid preparation for oral use which is easy to perform and which does not affect the drug efficacy and has excellent performance.

Description

[0001] ORAL SOLID COMPOSITE COMPRISING VALSARTAN [0002]

The present invention relates to oral solid preparations containing valsartan, and more particularly, to a method for preparing solid preparations comprising the steps of mixing valsartan with a bulking agent, And which does not affect the drug efficacy, and a method for producing the same.

Valsartan, an angiotensin receptor blocker (ARB) -based antihypertensive drug, is marketed as a combination of valsartan and a diuretic combination of hydrochlorothiazide and amlodipine besylate, a calcium channel blocker (CCB) .

In the case of the existing valsartan, it has been known that static electricity is generated severely and the flowability of the granule is not good when manufactured by the direct method, so that it is not applicable to mass production. Accordingly, a wet granulation method using a solvent, which is a generally known solidification manufacturing process, has been widely used for producing a solid preparation containing valsartan. However, when a solid preparation is prepared according to such a wet granulation method, there is a problem that the dissolution rate is not constant depending on the lot of production, and the dissolution pattern differs from that of Diovan, Codion or Expo designation of the original developer.

Korean Patent No. 10-0618038 discloses a method of preparing a solid preparation by dry granulation method in which valsartan is mixed with an active agent and an additive and then subjected to a pressing process. However, in the case of such a dry granulation method, there is a problem that disadvantages such as disintegration or elution may not be constant at the time of manufacture since a press time is prolonged due to the use of a presser and various variables are present depending on the pressing conditions. In addition, there is a drawback that it is difficult to economically and efficiently manage the process in case of a finished drug manufacturer because there is a risk of cross contamination due to the difficulty of washing the presser in general.

Therefore, research on the development of solid preparations for oral use of valsartan, which can process the tablet by the direct method instead of the dry granulation method or the wet granulation method without the pressing process and maintain the elution pattern of excellent performance by not affecting the efficacy of the tablet .

The present invention seeks to provide a solid oral formulation of valsartan having excellent flowability and dissolution performance so as to simplify the formulation process.

The present invention also provides a method for preparing the oral solid preparation of valsartan.

The present invention includes valsartan having a bulk density of from 0.28 to 0.35, wherein the valsartan has a particle size distribution of from 1 to 20 mu m particles of from 40 to 60% and a particle size of from 20 to 100 mu m of from 60 to 40% Lt; / RTI >

The present invention is also characterized in that the bulk density of valsartan is 0.28 to 0.35 and the particle size distribution is recrystallized to be 40% to 60% of particles having a particle size of 1 to 20 μm and 60% to 40% of particles having a particle size of 20 to 100 μm And a step of molding the tablets by the direct method using the active ingredient comprising the recrystallized valsartan.

Hereinafter, the present invention will be described in more detail.

The present invention is characterized in that bulk granules can be prepared only by mixing the excipient by controlling the volume density and the particle distribution of valsartan in the single and complex solid preparations of valsartan, which have been produced by the dry granulation method or the wet granulation method. This makes it possible to manufacture particles of valsartan which are easy to produce solid preparations and which do not affect the efficacy of the drug. In particular, the present invention is characterized by simplifying the formulation process of valsartan solid dosage forms, improving quality in mass production, and reducing processing time and cost.

In general, valsartan is a compound represented by the following formula (1), and its precise chemical name is (S) -N-valeryl-N - {[2 '- (1 H -tetrazol-5-yl) Methyl} -valine [(S) -N-valeryl-N - {[2 '- (lH- tertazol- 5- yl) biphenyl-4- yl] methyl} -valine].

[Chemical Formula 1]

The valsartan is usually prepared by a dry granulation method such as a compression process and is prepared by adding a single preparation having a dose of 80 mg to 160 mg per one unit and a solution containing 12.5 mg of hydrochlorothiazide or 6.94 mg to 13.87 mg of amlodipine besylate, Lt; RTI ID = 0.0 > oral < / RTI >

Accordingly, the present invention provides a solid preparation for oral administration, which is prepared by optimizing the particle distribution and the bulk density in a predetermined range for economical and easy process management of the oral solid preparation containing valsartan, and a preparation method thereof do.

Hereinafter, a solid preparation for oral use of valsartan and a preparation method thereof according to a specific embodiment of the present invention will be described in detail. It is to be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

In addition, throughout this specification, "comprising" or "containing ", unless specifically stated, refers to including any and all components (or components) Can not be interpreted as excluding.

Particularly, in a preferred embodiment of the present invention, the present invention includes valsartan having a volume density of from 0.28 to 0.35, wherein the valance composition has a particle size distribution of 1 to 20 mu m in a range of 40% to 60% Wherein the particles are 60% to 40%.

The volume density of valsartan may be 0.28 to 0.35, preferably 0.30 to 0.34, and the volume density of valsartan should be 0.28 or more from the viewpoint of ensuring excellent flowability in forming tablets. In order to maintain a good performance dissolution pattern The volume density of valsartan should be less than 0.35.

In addition, the valsartan may have a particle size distribution as described above in terms of solubility, that is, a dissolution rate, and preferably 1 to 10 탆 particles are 40% to 60%, 20 to 50 탆 particles are 60% to 40% Lt; / RTI > At this time, the average particle size of the valsartan may be 3 to 12 占 퐉, preferably 4 to 7 占 퐉 in consideration of the solubility, that is, the dissolution rate.

In the oral solid preparation of the present invention, the content of valsartan may be 20% to 65%, preferably 35% to 50%, based on the total weight of the whole preparation. The content of valsartan may be 20% or more in consideration of the tablet size, and may be 65% or less in terms of physical properties during manufacture.

The oral solid preparation may further contain at least one active ingredient selected from the group consisting of hydrochlorothiazide and amlodipine besylate as well as valsartan as an active ingredient.

The amlodipine besylate may have an average particle diameter of 10 to 20 占 퐉, preferably 12 to 16 占 퐉, and when prepared by the direct method, the elution rate is preferably 12 to 16 占 퐉 in terms of the dissolution rate. The particle size distribution of the amlodipine besylate may be 25 탆 or more, or 25 to 40 탆, preferably 30 탆 or 30 to 37 탆, which corresponds to 90% of the number of particles in terms of mixing and final dissolution And the particle size corresponding to 50% of the number of particles may be 10 to 15 탆, preferably 12 to 14 탆, and the particle size corresponding to 10% of the particle size is 5 탆 or less or 2 to 5 탆, preferably 4 Mu m or 3 to 4 mu m.

The average particle diameter of the hydrochlorothiazide may be 10 to 15 mu m, preferably 12 to 13 mu m, and it is preferable to use a raw material having an average particle diameter of 10 to 15 mu m in terms of dissolution rate. The particle size distribution of the hydrochlorothiazide may be 35 탆 or more, or 35 to 60 탆, preferably 40 탆 or 40 to 50 탆, which corresponds to 90% The particle size corresponding to the number of particles of 50% may be 15 to 20 占 퐉, preferably 12 to 13 占 퐉, and the particle size corresponding to 10% of the particle size may be 5 占 퐉 or less or 2 to 5 占 퐉, preferably 3 占 퐉 or less 2 to 3 mu m.

At this time, the active ingredient such as amlodipine besylate and hydrochlorothiazide may contain an amount of 3% to 10%, preferably 3% to 6%, based on the total weight of the whole preparation. The content of the additional active ingredient may be at least 3% in terms of the content ratio of valsartan, and may be less than 10% in terms of processability at the time of manufacture.

In addition, the solid preparation for oral use of the present invention are microcrystalline cellulose, star cap ^® 1500, Rudy Naples ^® (Ludipress ^®), the cross Carmel agarose, copovidone ^® VA 64, low-substituted hydroxypropyl cellulose, magnesium stearate, colloidal And at least one excipient selected from the group consisting of sulfur dioxide, talc, talc, glycoconjugate sodium, isomalt, lactose for direct use, and mannitol. At this time, the microcrystalline cellulose in the flowable side of the mixture during elution pattern and manufacture, star cap ^® 1500, Rudy Naples ^®, cross Carmel as agarose, copovidone ^® VA 64, low-substituted hydroxypropyl cellulose, magnesium stearate, colloidal And an excipient such as anhydrous silicon dioxide can be used.

The excipient may comprise an amount of 3% to 80%, preferably 5% to 60%, more preferably 30% to 50%, based on the total weight of the formulation. The content of the excipient may be 30% or more in terms of dissolution rate and processability, and may be 80% or less in terms of tablet size.

Solid formulations for the oral administration is in an amount of in particular, star cap ^® 1500 (Starcap ^® 1500) or Rudy Naples ^® 10% to 50% relative to (Ludipress ^®) throughout the formulation total weight, preferably from 20% to 40% . The low-substituted hydroxypropyl cellulose or croscarmellose may be contained in an amount of 3% to 20%, preferably 5% to 10%, based on the total weight of the whole preparation.

On the other hand, the present invention relates to a process for recrystallization in which the bulk density of valsartan is 0.28 to 0.35, the particle size distribution is 40% to 60% of particles of 1 to 20 μm and 60% to 40% of particles of 20 to 100 μm, The present invention provides a method of producing an oral solid preparation comprising a step of forming a tablet by a direct method using an active ingredient containing recrystallized valsartan.

The recrystallization may be carried out using at least one organic solvent selected from the group consisting of n-hexane (n-hexane), diethyl ether, dichloromethane and ethyl acetate.

The method may further comprise mixing the recrystallized valsartan with hydrochlorothiazide or amlodipine besylate. The hydrochlorothiazide has an average particle diameter of 10 to 15 占 퐉, a particle diameter of 35 占 퐉 or more corresponding to 90% of the particle count, a particle diameter of 15 to 20 占 퐉 corresponding to 50% of the particle count, a particle diameter of 10% Can be 5 탆 or less. The amlodipine besylate has an average particle diameter of 10 to 20 占 퐉, a particle diameter of 25 占 퐉 or more corresponding to 90% of the particle number, a particle diameter of 10 to 15 占 퐉 corresponding to 50% of the particle number, and a particle diameter of 10% 5 mu m or less.

In particular, the formulations of the present invention can be formed into solid formulations by a direct method, which involves titrating the excipient after mixing with valsartan. In general, valsartan is manufactured by wet granulation method or dry granulation method because it can not be manufactured by direct method. However, in the present invention, by adjusting the volume density and particle of valsartan to a predetermined range and combining the appropriate excipients, a solid preparation excellent in flow, pressure, and disintegration can be produced. Moreover, at the same time, the dissolution pattern of valsartan as a single agent and a composite agent can exhibit a pattern similar to that of the original developer with excellent performance.

Therefore, the present invention can shorten the manufacturing process and allow a uniform quality to be exhibited at the time of manufacture, thereby enabling economical and quality effects to be expected for the finished drug manufacturing company.

In the present invention, matters other than those described above can be added or subtracted as required, and therefore, the present invention is not particularly limited thereto.

In the present invention, it is possible to granulate the single and mixed solid preparations of valsartan, which have been produced by the dry granulation method or the wet granulation method, by adjusting the bulk density and particle distribution of valsartan, by only mixing the excipient. Thus, it is possible to effectively produce a solid preparation for oral use of valsartan which is easy to produce a solid preparation and does not affect the efficacy of the drug.

In addition, the present invention simplifies the formulation process of valsartan solid to improve quality in mass production, and to reduce processing time and cost.

1 to 2 are graphs showing the measurement results of the valsartan leaching test for Examples 1 to 3 and Comparative Examples 1 and 2.
Figs. 3 to 6 are graphs showing the measurement results of the valsartan elution test and the hydrochlorothiazide elution test for Examples 4 to 7. Fig.
Figs. 7 to 10 are graphs showing the measurement results of the valsartan dissolution test and the amlodipine besylate dissolution test for Examples 8 to 13. Fig.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited to the following examples.

Manufacturing example  One: Valsartan  Volume density and particle control step

Improved bulk density Valsartan  Recrystallization method ( Valsartan  A to C)

A 500 mL flask was charged with 10 volumes of ethyl acetate and 3 volumes of dichloromethane, followed by addition of 10 grams of valsartan and dissolution at a temperature of 40-50 DEG C for 2 hours. After completely dissolving, the mixture was cooled to 20 to 25 ° C and left for 4 hours. When solidification began to occur in the leftover mixed solution, stirring was started and 20 volumes of n-hexane was slowly added. When the addition of normal hexane was completed, the mixture was stirred at 20 to 25 ° C for 16 hours. The resulting solid was filtered and washed with normal hexane. The obtained white powder of valsartan was dried at 40 DEG C under a condition of 720 to 740 mmHg for 12 hours (yield: 86 to 90%).

mp 115-117 [deg.] C

(CD ₃ OD) 0.78 (9H, m), 1.19 (4H, m), 2.14 (2H, m), 2.46 (5 H, m), 7.51 (4 H, m); IR 2962, 1730, 1599, 1470, 1205 cm < ^{-1 &} gt ;.

The dried valsartan was sieved with a 425 μm sieve to obtain valsartan A to C having uniform particle size and improved bulk density (BD).

The bulk density, average particle size, particle size distribution, etc. of the thus-prepared valsartan AC were measured by the following methods, and the measured values were as shown in Table 1 below.

division Valsartan A Valsartan B Valsartan C Bulk density () 0.28 0.32 0.38 Average particle diameter (占 퐉) 12 5 2 Particle size distribution
(%) 1 to 20 μm 40 50 70 20 to 100 μm 60 50 30

Low bulk density ( Bulk Density ) Valsartan  Recrystallization method ( Valsartan  D)

A 250 mL flask was charged with 10 volumes of ethyl acetate and then 10 g of valsartan was added and the mixture was dissolved at a temperature of 40-50 DEG C for 1 hour. A 500-mL flask was charged with 25 volumes of n-hexane and stirred. To the flask, a solution of valsartan was added little by little. After the addition was completed, the mixture was stirred at room temperature for 18 hours, and the resulting solid was filtered and washed with n-hexane. The obtained white powder, valsartan, was dried at 40 ° C under 720-740 mmHg for 12 hours (yield: 93-95%).

mp 115-117 [deg.] C

(CD ₃ OD) 0.78 (9H, m), 1.19 (4H, m), 2.14 (2H, m), 2.46 (5 H, m), 7.51 (4 H, m); IR 2962, 1730, 1599, 1470, 1205 cm < ^{-1 &} gt ;.

The thus-prepared valsartan D was measured for volume density, average particle size, particle size distribution and the like by the same method as for valsartan A to C, and the measured values thereof are shown in Table 2 below.

The volume density, average particle diameter and particle size distribution of valsartan D thus produced are shown in Table 1 below.

division Valsartan D Bulk density () 0.26 Average particle diameter (占 퐉) 15 Particle size distribution
(%) 1 to 20 μm 30 20 to 100 μm 70

Manufacturing example  2: Of hydrochlorothiazide  Particle conditioning step

Through the crystallization process, crystals of hydrocroitrided grains having an average particle size of 12 탆 and a particle size of 39 탆 corresponding to 90% of the number of particles in the particle distribution were prepared.

Manufacturing example  3: Amlodipine Vesicular  Particle conditioning step

In a 1,000 mL flask, 80 g of amlodipine base was dissolved in 500 mL of anhydrous ethanol, and then 11.5 g of benzenesulfonic acid dissolved in 26 mL of absolute ethanol at 20 ° C was slowly added dropwise thereto at the same temperature. The mixture was stirred for one hour after the dropwise addition, and benzenesulfonic acid was added dropwise twice in the same manner and stirred. After the final stirring for 1 hour, the precipitated crystals were filtered, washed with anhydrous ethanol and isopropyl alcohol, and dried to give amlodipine besylate particles with improved crystals (yield: 80 to 85%). Particularly, when amorphous amlodipine besylate A having an average particle diameter of 16 탆 and a particle size distribution of 90% of 33 탆 and an average particle size of 7 탆 and a particle size distribution of 90% To prepare amlodipine besylate B having a particle diameter of 18 탆.

Example  1 to 3 and Comparative Example  1-2

In the composition shown in the following Table 3, the main component valsartan and the colloidal silicon dioxide were each dropped and mixed in a 30 mesh sieve. Microcrystalline cellulose, low-substituted hydroxypropylcellulose, and magnesium stearate were mixed in a 30-mesh sieve, followed by direct tableting using a rotary tablet press at a tabletting speed of 20 rpm. After this, by coating a tablet of the uncoated tablet dry state to the OPA ^® to prepare a solid dosage form for oral use.

division Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 chief ingredient Valsartan Kinds A B B C D Capacity (mg) 160.0 160.0 80.0 160.0 160.0 Excipient Microcrystalline cellulose (PH201, mg) 99.5 99.5 48.8 99.5 99.5 Disintegration Low substituted hydroxypropyl cellulose (mg) 30.0 30.0 15.0 30.0 30.0 Lubricant Colloidal silicon dioxide (mg) 1.5 1.5 0.7 1.5 1.5 Lubricant Magnesium stearate (mg) 9.0 9.0 4.5 9.0 9.0 Coated substrate Opadry ^® (mg) 12.0 12.0 6.0 12.0 12.0 Total Weight (mg) 312.0 312.0 155.0 312.0 312.0 Whether tabletable possible possible possible possible impossible Weight deviation ± 5 mg
Within ± 4 mg
Within ± 4 mg
Within ± 3 mg
Within ± 10 mg
Excess Disintegration About 2 minutes About 2 minutes About 2 minutes About 2 minutes About 2 minutes Hardness 14kp 14kp 11kp 14kp 14kp

As shown in Table 3, in Comparative Example 2, since the flowability of valsartan was poor, the weight deviation occurred during tableting, which made the operation difficult. In Examples 1 to 3 and Comparative Example 1, there was no problem in the tableting operation. That is, it can be seen that the bulk density of valsartan should be 0.28 or more so that the direct method can be manufactured.

Experimental Example  One

The oral solid preparations prepared according to Examples 1 to 3 and Comparative Example 1 were subjected to a dissolution test in the following manner.

Test Methods

The elution test was carried out in accordance with Method 2 (paddle method) described in Korean Pharmacopoeia Dissolution Test Method. Each test solution was prepared by the following method and the dissolution test was carried out with 900 mL of the test solution at 37 ± 0.5 ° C.

1) The pH 1.2 test solution was prepared by adding 7 mL of hydrochloric acid and 2 g of sodium chloride to 1 liter of water.

2) The pH 4.0 solution was adjusted to pH 4.0 with a 0.05% mol / L acetic acid buffer solution and 0.05 mol / L sodium acetate solution (41: 9).

3) To the test solution of pH 6.8, add 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution and 118 mL of 0.2 mol / L sodium hydroxide solution and water to make 1,000 mL.

4) 1 L of water was used as a test solution without a separate pH adjusting agent.

In particular, the eluate was collected at each time, filtered through a 0.45 μm membrane filter, diluted five times with each eluant, and absorbance was measured at a wavelength of 250 nm. At this time, Diovan was used as a control group at 160 mg and 80 mg. A graph of the measurement result is shown in Figs. 1 and 2.

As shown in Figs. 1 and 2, it can be seen that Examples 1 to 3 using valsartan A and B having a bulk density of 0.28 to 0.32 according to the present invention exhibit a dissolution rate similar to that of Diovan, which is a control group. However, in the case of Comparative Example 1 in which the bulk density of valsartan was 0.38, the dissolution rate was delayed in pH 1.2, pH 4.0, and water. As described above, it was confirmed that the higher the bulk density, the more smooth the tableting operation, but the slower the dissolution rate. Therefore, it can be seen that the dissolution rate is most similar to the product of the original developer, and the tableting operation can be smoothly performed by optimizing the bulk density and particle size distribution of valsartan to a predetermined range.

Example  4 to 7

Hydrocarbons such as valsartan C (volume density of 0.32), hydrochlorothiazide (average particle size of 12 占 퐉, within 90% of 39 占 퐉) and colloidal silicon dioxide were each dropped and compounded in a 30 mesh sieve as a main ingredient in the composition shown in the following Table 4 . The mixture of microcrystalline cellulose or star cap ^® 1500 or Rudy Naples ^® LCE and low substituted hydroxypropyl cellulose, and magnesium stearate were mixed Lower sieve 30 mesh Compression then using a rotary tablet press directly by tableting speed 20 rpm conditions in . After this, by coating a tablet of the uncoated tablet dry state to the OPA ^® to prepare a solid dosage form for oral use.

division Example 4 Example 5 Example 6 Example 7 chief ingredient Valsartan (mg) 160.0 160.0 160.0 80.0 chief ingredient Hydrochlorothiazide (mg) 12.5 12.5 12.5 12.5 Excipient Microcrystalline cellulose (mg) 20.0 20.0 30.0 15 Excipient Star cap ^® 1500 (mg) - - 66.5 34.0 Excipient Microcrystalline cellulose (for direct use, mg) - 56.5 - Excipient Rudy Naples ^® LCE (mg) 56.5 - - Disintegration Low substituted hydroxypropyl
Cellulose (mg) 40.0 40.0 20.0 10.0 Lubricant Colloidal silicon dioxide (mg) 2.0 2.0 2.0 1.0 Lubricant Magnesium stearate (mg) 9.0 9.0 9.0 4.5 Coated substrate Opadry ^® (mg) 12.0 12.0 12.0 6.0 Total Weight (mg) 312 312 312 163 Disintegration 1 minute 30 seconds 2 minutes 4 minutes 4 minutes Hardness 9kp 16kp 15kp 12kp

Experimental Example  2

The oral solid preparations prepared according to Examples 4 to 7 were subjected to a dissolution test in the following manner.

Test Methods

The dissolution test conditions were the same as in Experimental Example 1, and the eluate was taken and tested according to the dissolution test of USP 30 "Valsartan and Hydrochlorothiazide Tablets".

In particular, the eluate was collected at each time, filtered through a 0.45 μm membrane filter, diluted five times with each eluant, and absorbance was measured at a wavelength of 250 nm. At this time, 12.5 mg of Codiovan 160 and Codiovan 80 were used as a control group. The graphs of the measurement results are shown in Figs. 3 to 6.

As shown in FIGS. 3 to 6, the combination preparation of Examples 4 to 7, which contains valsartan and hydrochlorothiazide having a volume density of 0.32 according to the present invention, exhibits an excellent dissolution rate similar to that of the control groups CodiBAN 160 and 80 . In addition, the combined preparation of Examples 4 to 7 exhibited excellent flowability in the manufacturing process. In particular confirmed in Example 5 is valsartan and hydrochlorothiazide thiazides a medium dissolution rate this Example 6, and the dissolution rate is generally indicated a very similar pattern as the original developer goods 7 with star cap ^® 1500 excipients, showed high Respectively.

Example  8-13

(Average particle size of 16 mu m, average particle size of 33 mu m or less within 90%) or amlodipine besylate B (average particle size of 7 mu m, average particle size of 10 mu m or less) as main components, 18% within 90%), and colloidal silicon dioxide were each dropped and mixed in a 30 mesh sieve. To the mixture were added microcrystalline cellulose or Rudy Naples ^®, a low-substituted hydroxypropylcellulose or cross Carmel agarose or copovidone ^® VA 64, it makes a magnesium stearate sieve 30 mesh using a rotary tablet press in a mixture, and then tabletting speed 20 rpm . After this, by coating a tablet of the uncoated tablet dry state to the OPA ^® to prepare a solid dosage form for oral use.

Purpose of blending Ingredients Example 8 9 10 11 12 13 chief ingredient Valsartan (mg) 160.0 160.0 160.0 160.0 160.0 80 chief ingredient Amlodipine
Besylate Kinds A A A A B A Capacity (mg) 13.87 13.87 13.87 13.87 13.87 6.94 Excipient Microcrystalline cellulose (mg) 30.0 35.0 20.0 23.0 23.0 11.5 Excipient Microcrystalline cellulose
(Direct use, mg) 53.13 - - - - - Excipient Rudypless ^® (mg) - 58.13 52.13 61.13 61.13 30.56 Disintegration Low substituted hydroxypropyl
Cellulose (mg) 40.0 15.0 38.0 38.0 38.0 19.0 Disintegration Sodium croscarmellose sodium
(mg) - 15.0 - - - Disintegration Copovidone ^® VA64 (mg) - - 12.0 - - Lubricant Colloidal silicon dioxide (mg) 3.0 3.0 4.0 4.0 4.0 2.0 Lubricant Magnesium stearate (mg) 8.0 8.0 8.0 8.0 8.0 4.0 Coated substrate Opadry ^® (mg) 12.0 12.0 12.0 12.0 12.0 6.0 Total Weight (mg) 320.0 320.0 320.0 320.0 320.0 320.0 Disintegration 2 minutes 1 minute 3 minutes 1 minute 1 minute 1 minute Hardness 18kp 12kp 9kp 8kp 8kp 8kp

Experimental Example  3

The oral solid preparations prepared according to the above Examples 8 to 13 were subjected to a dissolution test by the following method.

Test Methods

The elution test conditions were the same as in Experimental Example 1, and the eluate was taken out, filtered through a 0.45 μm membrane filter, and analyzed by HPLC at a wavelength of 237 nm. As control, Exposure 10 and 5 were used as 160 mg and 80 mg, respectively. The graphs of the measurement results are shown in Figs. 7 to 10.

As shown in FIGS. 7 to 10, according to the present invention, the combined preparation of Examples 8 to 13 including valsartan and amlodipine besylate having a volume density of 0.32 exhibited an excellent dissolution rate similar to that of control pills 10 and 5 Able to know. In addition, the combination preparations of Examples 8 to 13 showed excellent flowability in the manufacturing process. Specifically, Examples 8 and 12 is very similar patterns and the product in the case of Examples 9, 11 and 13 used as were the intermediate dissolution value of amlodipine linen salts of water and pH 4.0 solution higher, Rudy Naples ^® excipient original creator Respectively.

As described above, according to the present invention, single and mixed solid preparations containing valsartan having a specific volume density and particle distribution optimized in a predetermined range can be easily tableted only by mixing the excipient. Thereby, it is possible to obtain an excellent effect that the preparation of the solid preparation is simple compared with the conventional dry granulation method or the wet granulation method, but does not affect the drug efficacy.

Claims (15)

Valsartan having a volume density of from 0.28 to 0.35,
Wherein the valsartan has a particle size distribution of 1 to 20 mu m particles of 40 to 60 wt% and a particle size of 20 to 100 mu m of 60 to 40 wt%. The method according to claim 1,
Wherein said valsartan has an average particle size of 3 to 12 占 퐉. The method according to claim 1,
Wherein the content of valsartan is 20% to 65% of the total weight of the preparation. The method according to claim 1,
Wherein the active ingredient further comprises at least one active ingredient selected from the group consisting of hydrochlorothiazide and amlodipine besylate. 5. The method of claim 4,
Wherein the content of the additional active ingredient is 3% to 10% based on the total weight of the whole preparation. 5. The method of claim 4,
Wherein the amlodipine besylate salt has an average particle diameter of 10 to 20 占 퐉, a particle diameter corresponding to the lower 90% of the particle number is 25 占 퐉 or more, a particle diameter corresponding to the lower 50% of the particle number is 10 to 15 占 퐉, % Of a particle diameter of 5 占 퐉 or less. 5. The method of claim 4,
Wherein the average particle diameter of the hydrochlorothiazide is 10 to 15 占 퐉, the particle diameter corresponding to the lower 90% of the particle number is 35 占 퐉 or more, the particle diameter corresponding to the lower 50% of the particle diameter is 15 to 20 占 퐉, And a particle size of 10 占 퐉 or less is 5 占 퐉 or less. The method according to claim 1,
But are not limited to, microcrystalline cellulose, pregelatinized starch, lactose, croscarmellose, vinylpyrinidone-vinyl acetate copolymer, low substituted hydroxypropylcellulose, magnesium stearate, colloidal silicon dioxide, talc, , Rectal lactose, and mannitol. ≪ RTI ID = 0.0 > 11. < / RTI > 9. The method of claim 8,
Wherein the content of the excipient is 3% to 80% based on the total weight of the whole preparation. The method according to claim 1,
Wherein the whole starch or lactose is present in an amount of 10% to 50% based on the total weight of the total preparation. The method according to claim 1,
Low substituted hydroxypropyl cellulose or croscarmellose in an amount of 5% to 20% based on the total weight of the total preparation. The volume density of valsartan is 0.28 to 0.35, the particle size distribution is 40 to 60% by weight of particles of 1 to 20 탆 and 60 to 40% by weight of particles of 20 to 100 탆, and
Molding the tablets by the direct method using the active ingredient comprising recrystallized valsartan
≪ / RTI > or a pharmaceutically acceptable salt thereof. 13. The method of claim 12,
Wherein the recrystallization step is carried out using at least one organic solvent selected from the group consisting of n-hexane, diethyl ether, dichloromethane, and ethyl acetate. 13. The method of claim 12,
Further comprising mixing said recrystallized valsartan with hydrochlorothiazide or amlodipine besylate. ≪ RTI ID = 0.0 > 11. < / RTI > 15. The method of claim 14,
The hydrochlorothiazide has an average particle diameter of 10 to 15 占 퐉, a particle diameter of 35 占 퐉 or less corresponding to the lower 90% of the number of particles, a particle diameter of 15 to 20 占 퐉 corresponding to the lower 50% of the number of particles, 10% of the particle diameter is 5 占 퐉 or less,
The amlodipine besylate has an average particle diameter of 10 to 20 占 퐉, a particle diameter of 25 占 퐉 or less corresponding to the lower 90% of the number of particles, a particle diameter of 10 to 15 占 퐉 corresponding to the lower 50% % Of a particle size of not more than 5 占 퐉.

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