WO2018088830A1

WO2018088830A1 - A pharmaceutical composition in a monolithic matrix tablet form comprising chlorthalidone or its salt and amlodipine or its salt and a process for preparing the same

Info

Publication number: WO2018088830A1
Application number: PCT/KR2017/012706
Authority: WO
Inventors: Jun-Hee Lee; Yong-Han Kim; Jae-Ryang JOO; Chang-Keun Hyun
Original assignee: Yuhan Corporation
Priority date: 2016-11-11
Filing date: 2017-11-10
Publication date: 2018-05-17
Also published as: KR20180053044A

Abstract

The present invention provides a pharmaceutical composition in a monolithic matrix tablet form, comprising granules containing chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt and a method for preparing the same. And also, the present invention provides a pharmaceutical composition in a bilayer tablet form, comprising a first layer in the monolithic matrix form and a second layer comprising telmisartan or its pharmaceutically acceptable salt and a method for preparing the same.

Description

A PHARMACEUTICAL COMPOSITION IN A MONOLITHIC MATRIX TABLET FORM COMPRISING CHLORTHALIDONE OR ITS SALT AND AMLODIPINE OR ITS SALT AND A PROCESS FOR PREPARING THE SAME

The present invention relates to a pharmaceutical composition in a monolithic matrix tablet form, comprising granules containing chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt and a method for preparing the same. And also, the present invention relates to a pharmaceutical composition in a bilayer tablet form, comprising a first layer in the monolithic matrix form and a second layer comprising telmisartan or its pharmaceutically acceptable salt and a method for preparing the same.

Hypertension is caused by various causes and therefore there are various studies on the combination formulations containing two or more antihypertensive drugs having different pharmacological mechanisms for the treatment thereof. For example, it has been reported that the combinations of a diuretic (such as hydrochlorothiazide and chlorthalidone), an angiotensin II receptor antagonist (such as olmesartan medoxomil and telmisartan), and/or a calcium channel blocker (such as amlodipine) can provide efficient hypertensive treatment effects.

As a formulation containing two or more antihypertensive drugs in a single dosage form, e.g., International Patent Publication No. WO 2003/059327 has disclosed a bilayer tablet comprising telmisartan and hydrochlorothiazide. And also, Korean Patent Publication No. 10-2011-0012732 has disclosed a rapidly disintegrating trilayer tablet consisting of a first layer comprising an angiotensin II receptor antagonist or a calcium channel blocker; a rapidly disintegrating second layer which is completely disintegrated in an aqueous medium within 1 minute; and a third layer comprising a diuretic. In addition, US Patent Publication No. 2007/0237815 has disclosed a tablet comprising amlodipine and chlorthalidone in specific amounts, the tablet of which has a structure of multi-segments including an inactive segment.

Meanwhile, in formulating a pharmaceutical composition in a single dosage form comprising the three active ingredients, a diuretic, an angiotensin II receptor antagonist, and a calcium channel blocker, it is required to minimize drug interactions and also to show bioequivalence to the respective formulations having each drug. As a method for avoiding the drug interaction, a formulation in a multi-layer tablet form where the three active ingredients are formulated in separate layers and inactive layers are inserted between each layer could be considered (for example, the formulation comprising an inactive segment as disclosed in US Patent Publication No. 2007/0237815). However, such a multi-layer tablet has the problems that it is difficult to apply at a production site due to the complicated manufacturing processes; and that it is difficult to ensure bioequivalence due to the dissolution changes of the respective drug which are derived from the complicated multi-layer structure.

Therefore, in formulating a pharmaceutical composition in a single dosage form comprising the three active ingredients, e.g., a diuretic, an angiotensin II receptor antagonist, and a calcium channel blocker, at least two active ingredients (e.g., chlorthalidone and amlodipine) are required to be formulated into a monolithic matrix form in order to avoid the multi-layer tablet form involving complicated manufacturing processes. Until now, however, no formulation in a monolithic matrix form comprising chlorthalidone or its salts and amlodipine or its salts has been developed. And also, no single dosage form in which a monolithic matrix comprising chlorthalidone or its salts and amlodipine or its salts is formulated along with a calcium channel blocker such as telmisartan or its salt has been developed.

Therefore, there is a need in the art to develop the combination formulation in a single dosage form which comprises a diuretic, an angiotensin II receptor antagonist, and a calcium channel blocker, especially chlorthalidone or its salt, amlodipine or its salt, and telmisartan or its salt, is readily applicable at the production site, and shows bioequivalence to the respective formulations having each active ingredient.

The present inventors carried out various researches in order to develop a formulation in a monolithic matrix form comprising chlorthalidone or its salt and amlodipine or its salt; and a formulation in a single dosage form in which the monolithic matrix is formulated in combination with telmisartan or its salt.

Chlorthalidone or its salt has low density, high dustiness and high electrostatic characteristics, so that it shows a tendency to cohere together or stick to the wall. In addition, the therapeutically effective content of chlorthalidone or its salt per unit formulation is about 25 mg as a free base, while the therapeutically effective content of amlodipine or its salt (for example, amlodipine besylate) per unit formulation is about 5 mg as a free base and about 6.9 mg as an amlodipine besylate. Therefore, because the high weight ratio and density differences between the active ingredients as well as the low weight ratios thereof per unit formulation make it very difficult to formulate the active ingredients into a monolithic matrix form through conventional formulation methods. That is, it has been found by the present invention that, when chlorthalidone or its salt (which has not only high dustiness and coherence but also remarkably high therapeutically effective contents in comparison with amlodipine or its salt) is mixed with amlodipine or its salt and then compressed into a monolithic matrix form, the tableting problems such as capping and sticking occurred and thus it is difficult to ensure content uniformity because the homogeneous mixing thereof is very difficult. And also, it is known in the art that amlodipine is unstable to moisture (Pharm. Dev. Technol. 2004, 9, (1):15-24). Therefore, since the granulation thereof affects unwanted effects on the stability thereof, it could be difficult to ensure the quality of the resulting formulation.

The present inventors carried out various researches in order to avoid the tableting problems and ensure content uniformity. Surprisingly, the present inventors have found that, when a tablet is prepared by granulating chlorthalidone or its salt, performing trituration of amlodipine or its salt, the granules and a pharmaceutically acceptable excipient and then compressing the mixture into a monolithic matrix tablet form, we can not only solve the tableting problems but also ensure the content uniformity, the bioequivalence to the respective formulations having each active ingredient, and the stability of each active ingredient. In addition, the present inventors have found that, when a single dosage form in a bilayer tablet form is prepared by forming a layer comprising telmisartan or its salt on the monolithic matrix, we can not only readily apply the process at the production site but also ensure the bioequivalence to the respective formulations having each active ingredient.

Therefore, the present invention provides a process for preparing a pharmaceutical composition in a monolithic matrix tablet form, the process of which comprises granulating chlorthalidone or its salt, performing trituration of amlodipine or its salt, the granules and a pharmaceutically acceptable excipient, and then compressing the mixture into a monolithic matrix tablet form; and a pharmaceutical composition in a monolithic matrix tablet form prepared therefrom.

And also, the present invention provides a process for preparing a pharmaceutical composition in a bilayer tablet form, the process of which comprises forming a layer comprising telmisartan or its salt on the monolithic matrix; and a pharmaceutical composition in a bilayer tablet form prepared therefrom.

In accordance with an aspect of the present invention, there is provided a pharmaceutical composition in a monolithic matrix tablet form, comprising granules containing chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt.

In accordance with another aspect of the present invention, there is provided a pharmaceutical composition in a bilayer tablet form, comprising a first layer in a monolithic matrix form comprising granules containing chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt; and a second layer comprising telmisartan or its pharmaceutically acceptable salt.

In accordance with still another aspect of the present invention, there is provided a process for preparing a pharmaceutical composition in a monolithic matrix tablet form comprising chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt, the process comprising: (a) granulating chlorthalidone or its pharmaceutically acceptable salt to prepare granules; (b) performing trituration of amlodipine or its pharmaceutically acceptable salt, the granules obtained in Step (a) and a pharmaceutically acceptable excipient to obtain a mixture; and (c) compressing the mixture obtained in Step (b) into a monolithic matrix tablet form.

In accordance with still another aspect of the present invention, there is provided a process for preparing a pharmaceutical composition in a bilayer tablet form comprising chlorthalidone or its pharmaceutically acceptable salt, amlodipine or its pharmaceutically acceptable salt, and telmisartan or its pharmaceutically acceptable salt, the process comprising: (a') granulating chlorthalidone or its pharmaceutically acceptable salt to prepare granules; (b') performing trituration of amlodipine or its pharmaceutically acceptable salt, the granules obtained in Step (a') and a pharmaceutically acceptable excipient to obtain a mixture; (c') compressing the mixture obtained in Step (b') into a layer in a monolithic matrix form to form a first layer; and (d') forming a second layer comprising telmisartan or its pharmaceutically acceptable salt on the first layer obtained in Step (c').

The pharmaceutical composition according to the present invention is prepared by granulating chlorthalidone or its salt, performing trituration of amlodipine or its salt, the granules and a pharmaceutically acceptable excipient and then compressing the mixture into a monolithic matrix tablet form. The pharmaceutical composition of the present invention makes it possible to avoid the tableting problems occurred in formulating chlorthalidone or its salt and amlodipine or its salt according to conventional methods. And also, the pharmaceutical composition of the present invention makes it possible to ensure the content uniformity, the bioequivalence to the respective formulations having each active ingredient, and the good stability. In addition, according to the present invention, the single dosage form in a bilayer tablet form is prepared by forming a layer comprising telmisartan or its salt on the monolithic matrix. Therefore, the pharmaceutical composition in the bilayer tablet according to the present invention makes it possible to ensure the bioequivalence to the respective formulations having each active ingredient and the good stability, as well as to be applied at the production site. Accordingly, the pharmaceutical composition in a monolithic matrix tablet form and the pharmaceutical composition in a bilayer tablet form according to the present invention can remarkably improve the patients' drug compliance.

FIG. 1 shows the blood concentration profiles of chlorthalidone obtained by oral administration of the bilayer tablet prepared according to the present invention and a reference formulation (Hygroton tablet) to beagle dogs.

FIG. 2 shows the blood concentration profiles of amlodipine obtained by oral administration of the bilayer tablet prepared according to the present invention and a reference formulation (Twynsta tablet) to beagle dogs.

FIG. 3 shows the blood concentration profiles of telmisartan obtained by oral administration of the bilayer tablet prepared according to the present invention and a reference formulation (Twynsta tablet) to beagle dogs.

FIG. 4 shows the appearances of the tablets of Comparative Example prepared by increasing the compressing pressure.

The present invention provides a pharmaceutical composition in a monolithic matrix tablet form, comprising granules containing chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt.

The present invention also provides a pharmaceutical composition in a bilayer tablet form, comprising a first layer in a monolithic matrix form comprising granules containing chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt; and a second layer comprising telmisartan or its pharmaceutically acceptable salt.

The present invention also provides a process for preparing a pharmaceutical composition in a monolithic matrix tablet form comprising chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt, the process comprising: (a) granulating chlorthalidone or its pharmaceutically acceptable salt to prepare granules; (b) performing trituration of amlodipine or its pharmaceutically acceptable salt, the granules obtained in Step (a) and a pharmaceutically acceptable excipient to obtain a mixture; and (c) compressing the mixture obtained in Step (b) into a monolithic matrix tablet form.

The present invention also provides a process for preparing a pharmaceutical composition in a bilayer tablet form comprising chlorthalidone or its pharmaceutically acceptable salt, amlodipine or its pharmaceutically acceptable salt, and telmisartan or its pharmaceutically acceptable salt, the process comprising: (a') granulating chlorthalidone or its pharmaceutically acceptable salt to prepare granules; (b') performing trituration of amlodipine or its pharmaceutically acceptable salt, the granules obtained in Step (a') and a pharmaceutically acceptable excipient to obtain a mixture; (c') compressing the mixture obtained in Step (b') into a layer in a monolithic matrix form to form a first layer; and (d') forming a second layer comprising telmisartan or its pharmaceutically acceptable salt on the first layer obtained in Step (c').

In the pharmaceutical composition in a monolithic matrix tablet form and the process for preparing the same, chlorthalidone or its pharmaceutically acceptable salt may be used in a therapeutically effective amount. Preferably, chlorthalidone or its pharmaceutically acceptable salt may be used so as to be present in an amount ranging from 12.5 mg to 25 mg as a free base per unit tablet. And also, amlodipine or its pharmaceutically acceptable salt may be used for example in the form of amlodipine besylate. Preferably, amlodipine or its pharmaceutically acceptable salt may be used so as to be present in an amount of 5 mg as a free base (in an amount of about 6.9 mg as amlodipine besylate) per unit tablet.

And also, in the pharmaceutical composition in a bilayer tablet form and the process for preparing the same, chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt may be used in the amounts as described in the above. And, telmisartan or its pharmaceutically acceptable salt may be used in a therapeutically effective amount. Preferably, telmisartan or its pharmaceutically acceptable salt may be used so as to be present in an amount ranging from 40 mg to 80 mg as a free base per unit tablet. For example, chlorthalidone or its pharmaceutically acceptable salt, amlodipine or its pharmaceutically acceptable salt, and telmisartan or its pharmaceutically acceptable salt may be used so as to be present in the amounts of 12.5/5/40 mg, 12.5/5/80 mg, 25/5/40 mg, or 25/5/80 mg as each free base per unit tablet, but not limited thereto.

The granulating in Step (a) and Step (a') may be carried out by conventional granulation methods used in the field of pharmaceutics, preferably by wet granulation including the use of a binder solution. For example, the granulating of chlorthalidone or its pharmaceutically acceptable salt in Step (a) and Step (a') may be performed by using an appropriate diluent, disintegrant, and binder.

The diluent may be one or more selected from the group consisting of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate, cellulose acetate phthalate, dibasic calcium phosphate or its hydrates, lactose, polyethylene oxide, polyvinyl acetate, polyvinyl alcohol, povidone, corn starch, potato starch, pregelatinized starch, hydroxyethyl starch, dextrin, dextran, maltodextrin, polydextrose, guar gum, locust bean gum, xanthan gum, cyclodextrin, gum arabic, gellan gum, karaya gum, casein, tara gum, tamarind gum, tragacanth gum, ghatti gum, gelatin, collagen, protamine, carbomer, polyacrylamide, carnauba wax, beeswax, sucrose, liquid sucrose, polyvinyl acetate, diethylaminoacetate, chitosan, chitin, agar, pectin, carrageenan, shellac, microcrystalline cellulose, sodium citrate, calcium phosphate, glycine, starch, mannitol, carboxymethylcellulose, erythritol, isomalt, maltitol, xylitol, sorbitol, trehalose, dextrose, and low-substituted hydroxypropyl cellulose. Preferably, the diluent may be microcrystalline cellulose.

The disintegrant may be one or more selected from the group consisting of crospovidone, copovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, casein formaldehyde, chitin, chitosan, polymerized agar acrylamide, xylan, smecta, modified tapioca starch, alginic acid or its salt, hydroxypropyl cellulose, polacrilin potassium, starch, pregelatinized starch, and carboxymethyl starch. Preferably, the disintegrant may be sodium starch glycolate.

The binder may be one or more selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sucrose, gelatin, acacia gum, povidone, hypromellose, copovidone, starch, glucose syrup, polyethylene glycol 6000, methyl cellulose, ethyl cellulose, carboxymethylcellulose, hydroxyethyl cellulose, low-substituted hydroxypropyl cellulose, and methylcellulose. Preferably, the binder may be povidone. The binder may be used in a binder solution form dissolved in water, an organic solvent (e.g., ethanol, isopropanol, methylene chloride, and so on), or a mixed solvent of water and an organic solvent.

It is preferable that the granules obtained in Step (a) and Step (a') preferably have an appropriate particle size. For example, it is preferable to control the d_(0.9) of the granules (i.e., the average diameter of the 90% granules) to 250 to 800 ㎛. The particle size control may be performed by a sieving process using an equipment such as Fitz mill (Fitz patrick, USA).

And also, the granules obtained in Step (a) and Step (a'), i.e., the granules containing chlorthalidone or its pharmaceutically acceptable salt, may be present preferably in an amount ranging from 20 to 80 % by weight, based on the total weight of the monolithic matrix tablet or based on the total weight of the first layer in a monolithic matrix form, for providing suitable degree of mixing in the final mixture and appropriate hardness.

The pharmaceutically acceptable excipient used in Step (b) and Step (b') includes one or more diluents selected from the group consisting of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate, cellulose acetate phthalate, dibasic calcium phosphate or its hydrates, lactose, polyethylene oxide, polyvinyl acetate, polyvinyl alcohol, povidone, corn starch, potato starch, pregelatinized starch, hydroxyethyl starch, dextrin, dextran, maltodextrin, polydextrose, guar gum, locust bean gum, xanthan gum, cyclodextrin, gum arabic, gellan gum, karaya gum, casein, tara gum, tamarind gum, tragacanth gum, ghatti gum, gelatin, collagen, protamine, carbomer, polyacrylamide, carnauba wax, beeswax, sucrose, liquid sucrose, polyvinyl acetate, diethylaminoacetate, chitosan, chitin, agar, pectin, carrageenan, shellac, microcrystalline cellulose, sodium citrate, calcium phosphate, glycine, starch, mannitol, carboxymethylcellulose, erythritol, isomalt, maltitol, xylitol, sorbitol, trehalose, dextrose, and low-substituted hydroxypropyl cellulose; one or more disintegrants selected from the group consisting of crospovidone, copovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, casein formaldehyde, chitin, chitosan, polymerized agar acrylamide, xylan, smecta, modified tapioca starch, alginic acid or its salt, hydroxypropyl cellulose, polacrilin potassium, starch, pregelatinized starch, and carboxymethyl starch; one or more lubricants selected from the group consisting of stearic acid or its salt, talc, light anhydrous silicic acid, magnesium oxide, magnesium silicate, magnesium aluminum silicate, titanium dioxide, sodium stearyl fumarate, aluminum silicate, colloidal silicon dioxide, and sucrose fatty acid ester; a coloring agent. In an embodiment, the pharmaceutically acceptable excipient used in Step (b) and Step (b') comprises microcrystalline cellulose, dibasic calcium phosphate, sodium starch glycolate, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, and a coloring agent.

The trituration in Step (b) and Step (b') includes any and all methods capable of providing a uniform mixture by stepwise combining the granules obtained in Step (a) and Step (a'), amlodipine or its pharmaceutically acceptable salt, and the pharmaceutically acceptable excipient. In an embodiment, the trituration may be carried out by a process comprising (i) mixing sodium starch glycolate and amlodipine or its pharmaceutically acceptable salt to obtain a first mixture, (ii) mixing the first mixture, pregelatinized starch, colloidal silicon dioxide, and a coloring agent to obtain a second mixture, (iii) mixing the second mixture and the granules obtained in Step (a) or Step (a') to obtain a third mixture, (iv) mixing the third mixture, microcrystalline cellulose, and dibasic calcium phosphate to obtain a fourth mixture, and (v) mixing the fourth mixture and magnesium stearate to obtain a final mixture.

It is preferable that the mixture obtained in Step (b) and Step (b') has a flowability suitable for carrying out the compressing step. For example, it is preferable that the mixture has 25% or less of Carr's Index. The Carr's Index, which is used for indicating the fluidity/flowability of powder, may be measured according to known methods (for example, R.L. Carr., "Evaluating Flow Properties of Solids", Chem. Eng. 72. 163-8. 1965). When the mixture obtained in Step (b) and Step (b') has 25% or less, preferably about 14 to 25 %, of Carr's Index according to the present invention, the mixture exhibits excellent flowability, which is suitable for carrying out the compressing step at the production site.

In the process of the present invention, the compressing in Step (c) and Step (c') is performed preferably under a compressing pressure for providing the monolithic matrix tablet or the first layer having hardness ranging from 7 to 30 kp. The compressing pressure varies depending on the type of the compressing machines and therefore can be appropriately adjusted to provide the hardness range described in the above. If the hardness is lower than the hardness range described in the above, the tablets may easily broken or damaged during the transportation, storage, and distribution thereof. If the hardness exceeds the hardness range described in the above, disintegration and/or dissolution thereof may be delayed.

In the pharmaceutical composition in a bilayer tablet form of the present invention, the forming a second layer may be carried out according to known methods for preparing a telmisartan-containing bilayer tablet, for example, according to the methods disclosed in WO 2003/059327. In an embodiment, the forming a second layer may be carried out by a process comprising (i') dissolving telmisartan or its pharmaceutically acceptable salt, sodium hydroxide, meglumine, and povidone in a mixed solvent of water and ethanol to prepare a binder solution; (ii') spraying the binder solution prepared in Step (i') on mannitol to prepare granules, (iii') mixing the granules prepared in Step (ii'), mannitol, and lubricant, and (iv') compressing the mixture obtained in Step (iii') on the first layer.

The pharmaceutical composition in a monolithic matrix tablet form and the pharmaceutical composition in a bilayer tablet form may comprise an additional coating layer, e.g., an additional film coating layer, for improving the appearance and the like. The film coating may be performed according to conventional methods therefor.

The present invention will be described in further detail with reference to the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Examples 1 to 6: Tablets containing chlorthalidone and amlodipine

The matrix tablets containing chlorthalidone and amlodipine were prepared according to the components and amounts shown in Table 1. The amounts of Table 1 represent the weight (mg) of each component per unit tablet.

Povidone was dissolved in purified water to prepare a binder solution. Chlorthalidone, sodium starch glycolate and microcrystalline cellulose were added to the granulator (Bohle, VMA-10, Germany), followed by preparing granules with the binder solution. The obtained granules were sieved with Fitz mill (Bohle, BTM-300, Germany) having 1.0 mm of screen size.

Sodium starch glycolate sieved with a No. 40 sieve was mixed with amlodipine besylate. Ferric oxide (red) sieved with a No. 60 sieve, pregelatinized starch, and colloidal silicon dioxide were mixed with the mixture. The chlorthalidone-containing granules obtained in the above were mixed with the mixture, followed by additionally mixing microcrystalline cellulose and dibasic calcium phosphate hydrated therewith. At this time, microcrystalline cellulose was used in the appropriate amount so that the total weight thereof in the unit tablet becomes 200 mg. Magnesium stearate sieved with a No. 40 sieve was mixed with the above mixture. The resulting mixture was compressed with the compressing machine (Oystar Manesty, Flexiteb, UK) to prepare the tablets having about 17 kp of hardness.

Table 1

Examples 7 to 10: Tablets containing chlorthalidone and amlodipine having different hardnesses

The tablets were prepared in accordance with the same procedures as in Example 2, except that each compression was performed so as to obtain the tablets having 7 kp of hardness (Example 7), the tablets having 10 kp of hardness (Example 8), the tablets having 20 kp of hardness (Example 9), and the tablets having 30 kp of hardness (Example 10), respectively.

Examples 11 to 13: Bilayer tablets containing chlorthalidone , amlodipine, and telmisartan

The bilayer tablets containing chlorthalidone, amlodipine, and telmisartan were prepared according to the components and amounts shown in Table 2. The amounts of Table 2 represent the weight (mg) of each component per unit tablet.

Telmisartan, sodium hydroxide, meglumine, and povidone were dissolved in a mixed solvent of purified water and ethanol to prepare a binder solution. While flowing mannitol in the fluidized bed granulator (Grlatt, GPCG-1, Germany), the binder solution was sprayed thereon to prepare granules. The obtained granules were sieved with a No. 18 sieve. Mannitol was added to the granules and then magnesium stearate and sodium stearyl fumarate sieved with a No. 40 sieve were added thereto, followed by mixing the resulting mixture.

The matrix tablet of Example 2 (as a upper layer) and the mixture of Table 2 (as a lower layer) were compressed with the compressing machine (Oystar Manesty, Flexiteb, UK) to prepare the bilayer tablets having about 17 kp of hardness.

Table 2

Comparative Examples 1 and 2: Tablets containing chlorthalidone and amlodipine having different weight ratios of the chlorthalidone -containing granules

The tablets were prepared in accordance with the same procedures as in Examples 1 to 6, according to the components and amounts shown in Table 3. The amounts of Table 3 represent the weight (mg) of each component per unit tablet.

Table 3

Comparative Examples 3 and 4: Tablets containing chlorthalidone and amlodipine having different particle sizes of the chlorthalidone -containing granules

The tablets were prepared in accordance with the same procedures as in Example 2, except that the sieving of the obtained granules was performed with Fitz mill (Bohle, BTM-300, Germany) having 0.5 mm of screen size (Comparative Example 3) and having 1.5 mm of screen size (Comparative Example 4), respectively.

Comparative Example 5: Tablets containing chlorthalidone and amlodipine prepared through trituration , without performing a granulation process

The matrix tablets were prepared according to the components and amounts shown in Table 4. The amounts of Table 4 represent the weight (mg) of each component per unit tablet. Sodium starch glycolate sieved with a No. 40 sieve was mixed with amlodipine besylate. Ferric oxide (red) sieved with a No. 60 sieve, pregelatinized starch, and colloidal silicon dioxide were mixed with the mixture. Chlorthalidone and povidone were mixed with the mixture, followed by additionally mixing microcrystalline cellulose and dibasic calcium phosphate hydrated therewith. Magnesium stearate sieved with a No. 40 sieve was mixed with the above mixture. The resulting mixture was compressed in accordance with the same method as in Examples 1 to 6 to prepare the tablets.

Table 4

Comparative Example 6: Tablets containing chlorthalidone and amlodipine prepared through simple mixing (non- trituration )

The matrix tablets were prepared according to the components and amounts shown in Table 5. The amounts of Table 5 represent the weight (mg) of each component per unit tablet. The chlorthalidone-containing granules were prepared in accordance with the same procedures as in Examples 1 to 6. And then, the tablets were prepared in accordance with the same procedures as in Examples 1 to 6, except that all excipients including the chlorthalidone-containing granules were sufficiently mixed each other at one time (i.e., without performing the trituration) in the post-mixing step.

Table 5

Comparative 7 and 8: Tablets containing chlorthalidone and amlodipine having different hardnesses

The tablets were prepared in accordance with the same procedures as in Example 3, except that each compression was performed so as to obtain the tablets having 6 kp of hardness (Comparative Example 7) and the tablets having 32 kp of hardness (Comparative Example 8), respectively.

Experimental Example 1: Particle size distribution test of the chlorthalidone-containing granules

Particle size distribution tests for the chlorthalidone-containing granules obtained in Examples 1 to 4 and Comparative Examples 1 to 4 were carried out according to the US Pharmacopoeia. Specifically, the particle size distribution test was performed according to the "<786> particle size distribution estimation by analytical sieving" method in the USP Physical Tests, using the ATM Sonic Sifter (L3P, ATM corporation, USA) model in the Test Sieve Shaker. Based on the results of the particle size distribution tests, each average diameter of 90% of the granules, i.e., d_(0.9), was calculated through the cumulative distribution thereof. The results are shown in Table 6 below.

Table 6

As shown in the results of Table 6, it can be seen that the chlorthalidone-containing granules of Examples 1 to 4 obtained according to the present invention can ensure the d_(0.9) value in the range from about 250 to 800 ㎛. On the other hand, Comparative Examples 3 and 4 showed the d_(0.9) values of 132 ㎛ and 1156 ㎛, respectively. These too small or large particle sizes make the particles be easily separated into smaller or larger particles in the final mixture; and show unfavorable characteristics in content uniformity and flowability of the mixture, which adversely affects quality of the product. It can be confirmed that the particle size distribution of the chlorthalidone-containing granules obtained according to the present invention can be favorably applied at the production site.

Experimental Example 2: Evaluation of flowability

For the mixtures right before the compressing step in Examples 1 to 4 and Comparative Examples 1, 3, 5, and 6, the Carr's Indexes (CI values) thereof were measured based on the following formula, according to the method reported by R.L Carr. et al. ("Evaluating Flow Properties of Solids", Chem. Eng. 72. 163-8. 1965). The results thereof are shown in Table 7.

Carr's Index = 100 x (Vb-Vt)/Vb

[Vb = bulk density, Vt = tapped density]

Table 7

As shown in the results of Table 7, it can be seen that the mixtures of Examples 1 to 4 obtained according to the present invention showed about 25% or less of the CI values, while the mixture obtained without performing a granulation process (Comparative Example 5) and the mixture obtained without performing a trituration (Comparative Example 6) showed the high CI values, i.e., low flowability. And also, the mixture of Comparative Example 1, where the weight ratio of the chlorthalidone-containing granules is very low (15% by weight with respect to the total weight of the mixture), showed insufficient improving effects on the properties of chlorthalidone (e.g., high dustiness, low density and high electrostatic characteristics) and therefore poor flowability which is unsuitable for performing the compressing step. In addition, Comparative Example 3 also showed low flowability due to the production of granules having relatively small size. It is generally known in the art that, when a CI value is 25% or less, good flowability is exhibited. Therefore, it can be seen that the mixtures of Examples 1 to 4 obtained according to the present invention exhibit excellent flowability which is suitable for carrying out the process step at the production site.

Experimental Example 3: Content uniformity test

Content uniformity tests were carried out using HPCL under the following analysis conditions, for the 10 tablets respectively taken from the tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 6. The results thereof are shown in Tables 8 to 10. In Tables 8 to 10, A and C represent the contents (the HPLC areas) of amlodipine and chlorthalidone, respectively.

- Detector: UV absorbance detector (wavelength 237 nm)

- Column: stainless-steel column (3.9 mm x 15 cm) packed with octadecyl-silanized silica gel (5 ㎛ in particle diameter)

- Mobile phase: methanol : acetonitrile : Mobile phase A = 31 : 15 : 30

(Mobile phase A was prepared by dissolving 7.0 mL of triethylamine in 900 mL of water, adjusting the pH to pH 3.0 with phosphoric acid, and then adding water to make 1000 mL.)

- Flow rate: 1 mL/min

- Injection volume: 50 μL

- Detector: UV absorbance detector (wavelength 254 nm)

- Column: stainless-steel column (4.6 mm x 25 cm) packed with octadecyl-silanized silica gel (5 ㎛ in particle diameter)

- Mobile phase: methanol : 0.01 M ammonium dihydrogen phosphate = 40 : 60 (the pH was adjusted to pH 5.5 with phosphoric acid.)

- Flow rate: 1.0 mL/min

- Injection volume: 25 μL

Table 8

Table 9

Table 10

As shown in the results of Tables 8 to 10, the tablets of Comparative Example 5 prepared without performing a granulation process showed very high variation in chlorthalidone contents, i.e., very low content uniformity of chlorthalidone; and the tablets of Comparative Example 6 prepared without performing a trituration showed very high variation in amlodipine contents, i.e., very low content uniformity of amlodipine. And also, the tablets of Comparative Example 1 having low weight ratio of the chlorthalidone-containing granules showed low content uniformity of the active ingredients due to poor flowability derived from insufficient improving effects on the properties of chlorthalidone. The tablets of Comparative Example 2 having high weight ratio of the chlorthalidone-containing granules showed very high variation in amlodipine contents, because amlodipine having relatively low weight ratio could not be mixed homogeneously. The tablets of Comparative Example 3 having small particle size of the chlorthalidone-containing granules and the tablets of Comparative Example 4 having large particle size of the chlorthalidone-containing granules did not provide the homogeneous mixing due to large size difference between the particles within the respective mixture and therefore showed low content uniformity of chlorthalidone and amlodipine. On the contrary, it can be seen that the tablets of Examples 1 to 4 obtained according to the present invention showed excellent content uniformity.

Experimental Example 4: Hardness and friability tests

Hardness tests, the friability tests and disintegration tests for the tablets prepared in Example 2 and 7 to 10 and Comparative Example 5, 7 and 8 were carried out according to the methods described in the 11th edition of the Korean Pharmacopoeia. The results thereof are shown in Table 11.

Table 11

As shown in the results of Table 11, the tablets of Examples 2 and 7 to 10 showed excellent properties in terms of the friability. The tablets of Comparative Example 7 showed low hardness and relatively high friability. The tablets of Comparative Example 8 showed low friability. However, the maximum value of the compressing pressure of the compressing machine was required for preparing the tablets, which may cause mechanical overload and exhibit low quality due to the delayed disintegration time. The tablets of Comparative Example 5 prepared without performing a granulation process of chlorthalidone showed low hardness and high friability and therefore exhibited low quality. When the compressing pressure was increased in order to increase the hardness thereof, tableting problems such as capping and laminating occurred and thus the effective production thereof could not be carried out (see FIG. 4). On the contrary, the tablets of Examples 2 and 7 to 10 prepared according to the present invention showed good hardness from about 7 to 30 kp and exhibited excellent productivity without tableting problems.

Experimental Example 5: Dissolution test

Dissolution test for the bilayer tablets prepared in Example 11 was carried out under the following conditions.

- Dissolution medium: 900mL of First Fluid (pH 1.2) for Disintegration Test in the 11th edition of the Korean Pharmacopoeia and 900mL of Second Fluid (pH 6.8) for Disintegration Test in the 11th edition of the Korean Pharmacopoeia

- Apparatus: Dissolution Test Method II (paddle method) in the 11th edition of the Korean Pharmacopoeia, 75rpm

- Temperature: 37 ℃

- Sampling Time: 5, 10, 15, 30, 45, 60, 90, and 120 minutes

The contents of amlodipine and chlorthalidone in the samples obtained from the above dissolution test were measured with HPLC according to the same manner as described in Experimental Example 3. In addition, the content of telmisartan in the samples was measured with HPLC under the following analysis conditions.

- Detector: UV absorbance detector (wavelength 298 nm)

- Column: stainless-steel column (4.0 mm x 4 cm) packed with octadecyl-silanized silica gel (5 ㎛ in particle diameter)

- Mobile phase: methanol : Mobile phase A = 70 : 30

(Mobile phase A was prepared by dissolving 2.0 g of ammonium dihydrogen phosphate in 900 mL of water, adjusting the pH to pH 3.0 with phosphoric acid, and then adding water to make 1000 mL.)

- Flow rate: 0.7 mL/min

- Injection volume: 5 μL

- Temperature of column: 40℃

Commercially available Twynsta tablets (Boehringer Ingelheim, amlodipine/telmisartan combination tablets) and Hygroton tablets (Hanlim pharmaceutical Inc., chlorthalidone tablets) were used as reference formulations. The results of the dissolution tests are shown in Table 12.

Table 12

As shown in the results of Table 12, it can be seen that the tablets prepared according to the present invention showed equivalent patterns in the dissolutions of amlodipine, telmisartan, and chlorthalidone, to the reference formulations.

Experimental Example 6: Stability test

The tablets prepared in Example 2 and the bilayer tablets prepared in Example 11 were packaged in Alu-Alu blister pack and stored under an accelerated condition (temperature 40℃, relative humidity 75%) and a room temperature condition (temperature 25℃, relative humidity 60%), respectively. The contents thereof were measured and the results thereof are shown in Table 13.

Table 13

As shown in the results of Table 13, it can be seen that the monolithic matrix tablets and the bilayer tablets prepared according to the present invention showed excellent stability.

Experimental Example 7: Evaluation of bioavailability

The bioavailabilities of the tablet prepared in Example 11 and the reference formulations were evaluated in beagle dogs. Sixteen beagle dogs weighing about 10 kg fasted for 12 hours were orally administered with the reference formulations and the tablet prepared in Example 11. The blood samples were collected with a heparinized syringe at 0.33, 0.67, 1, 1.5, 2, 3, 4, 6 and 8 hours after the administration. The collected blood samples were placed in a centrifuge tube and centrifuged at 3000 rpm for 5 minutes. The separated plasma samples were taken and stored frozen at -20℃ until the analysis thereof. The concentrations of telmisartan, amlodipine, and chlorthalidone in plasma were quantitated using LC/MS/MS under the following conditions.

1. LC conditions

- Guard column: Phenomenex C18 (4.0 x 3.0 mm I.D)

- Column temperature: about 40 ℃

2. MS/MS conditions

- Scan type: MRM (Multiple Reaction Monitoring) mode

- Polarity: Positive (telmisartan, amlodipine), Negative (chlorthalidone)

- Ion source: Electrospray ionization

- Resolution Q1: Unit

- Resolution Q3: Unit

The blood concentration profiles of chlorthalidone, amlodipine, and telmisartan obtained as in described above are shown in FIGs. 1 to 3, and the pharmacokinetic parameters and the T/R ratios are shown in Table 14.

Table 14

As shown in the results of FIGs. 1 to 3 and Table 14, it can be seen that the bilayer tablet prepared according to the present invention showed no statistically significant difference in the maximum blood concentration (Cmax) and the area under the curve (AUC) compared with the reference formulations (Twynsta tablet and Hygroton tablet) and therefore showed biological equivalence thereto.

Claims

A pharmaceutical composition in a monolithic matrix tablet form, comprising granules containing chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt.
A pharmaceutical composition in a bilayer tablet form, comprising a first layer in a monolithic matrix form comprising granules containing chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt; and a second layer comprising telmisartan or its pharmaceutically acceptable salt.
The pharmaceutical composition according to claim 1, wherein the amount of chlorthalidone or its pharmaceutically acceptable salt is 12.5 mg to 25 mg as a free base per unit tablet; and the amount of amlodipine or its pharmaceutically acceptable salt is 5 mg as a free base per unit tablet.
The pharmaceutical composition according to claim 2, wherein the amount of chlorthalidone or its pharmaceutically acceptable salt is 12.5 mg to 25 mg as a free base per unit tablet; the amount of amlodipine or its pharmaceutically acceptable salt is 5 mg as a free base per unit tablet; and the amount of telmisartan or its pharmaceutically acceptable salt is 40 mg to 80 mg as a free base per unit tablet.
The pharmaceutical composition according to claim 1 or 2, wherein the granules containing chlorthalidone or its pharmaceutically acceptable salt comprise chlorthalidone or its pharmaceutically acceptable salt, microcrystalline cellulose, sodium starch glycolate, and povidone.
The pharmaceutical composition according to claim 1 or 2, wherein the granules containing chlorthalidone or its pharmaceutically acceptable salt have 250 to 800 ㎛ of d_(0.9).
The pharmaceutical composition according to claim 1 or 2, wherein the granules containing chlorthalidone or its pharmaceutically acceptable salt are present in an amount ranging from 20 to 80 % by weight, based on the total weight of the monolithic matrix tablet or based on the total weight of the first layer in a monolithic matrix form.
The pharmaceutical composition according to claim 1 or 2, wherein the monolithic matrix tablet or the first layer in a monolithic matrix form further comprise microcrystalline cellulose, dibasic calcium phosphate, sodium starch glycolate, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, and a coloring agent.
The pharmaceutical composition according to claim 1 or 2, wherein the monolithic matrix tablet or the first layer in a monolithic matrix form has hardness ranging from 7 to 30 kp.
The pharmaceutical composition according to claim 2, wherein the second layer further comprises sodium hydroxide, meglumine, povidone, mannitol, and a lubricant.
A process for preparing a pharmaceutical composition in a monolithic matrix tablet form comprising chlorthalidone or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt, the process comprising:

(a) granulating chlorthalidone or its pharmaceutically acceptable salt to prepare granules;

(b) performing trituration of amlodipine or its pharmaceutically acceptable salt, the granules obtained in Step (a) and a pharmaceutically acceptable excipient to obtain a mixture; and

(c) compressing the mixture obtained in Step (b) into a monolithic matrix tablet form.
A process for preparing a pharmaceutical composition in a bilayer tablet form comprising chlorthalidone or its pharmaceutically acceptable salt, amlodipine or its pharmaceutically acceptable salt, and telmisartan or its pharmaceutically acceptable salt, the process comprising:

(a') granulating chlorthalidone or its pharmaceutically acceptable salt to prepare granules;

(b') performing trituration of amlodipine or its pharmaceutically acceptable salt, the granules obtained in Step (a') and a pharmaceutically acceptable excipient to obtain a mixture;

(c') compressing the mixture obtained in Step (b') into a layer in a monolithic matrix form to form a first layer; and

(d') forming a second layer comprising telmisartan or its pharmaceutically acceptable salt on the first layer obtained in Step (c').
The process according to claim 11, wherein the chlorthalidone or its pharmaceutically acceptable salt is used so as to be present in an amount ranging from 12.5 mg to 25 mg as a free base per unit tablet; and the amlodipine or its pharmaceutically acceptable salt is used so as to be present in an amount of 5 mg as a free base per unit tablet.
The process according to claim 12, wherein the chlorthalidone or its pharmaceutically acceptable salt is used so as to be present in an amount ranging from 12.5 mg to 25 mg as a free base per unit tablet; the amlodipine or its pharmaceutically acceptable salt is used so as to be present in an amount of 5 mg as a free base per unit tablet; and the telmisartan or its pharmaceutically acceptable salt is used so as to be present in an amount ranging from 40 mg to 80 mg as a free base per unit tablet.
The process according to claim 11 or 12, wherein the granulating in Step (a) and Step (a') is carried out by wet granulation.
The process according to claim 11 or 12, wherein the granulating in Step (a) and Step (a') is carried out by using chlorthalidone or its pharmaceutically acceptable salt, microcrystalline cellulose, sodium starch glycolate, and povidone.
The process according to claim 15, wherein the povidone is used in a binder solution form dissolved in water, an organic solvent, or a mixed solvent of water and an organic solvent.
The process according to claim 11 or 12, further comprising a sieving step for providing the granules having 250 to 800 ㎛ of d_(0.9) in Step (a) and Step (a').
The process according to claim 11 or 12, wherein the pharmaceutically acceptable excipient used in Step (b) and Step (b') comprises microcrystalline cellulose, dibasic calcium phosphate, sodium starch glycolate, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, and a coloring agent.
The process according to claim 11 or 12, wherein the trituration in Step (b) and Step (b') is carried out by a process comprising (i) mixing sodium starch glycolate and amlodipine or its pharmaceutically acceptable salt to obtain a first mixture, (ii) mixing the first mixture, pregelatinized starch, colloidal silicon dioxide, and a coloring agent to obtain a second mixture, (iii) mixing the second mixture and the granules obtained in Step (a) or Step (a') to obtain a third mixture, (iv) mixing the third mixture, microcrystalline cellulose, and dibasic calcium phosphate to obtain a fourth mixture, and (v) mixing the fourth mixture and magnesium stearate to obtain a final mixture.
The process according to claim 11 or 12, wherein the mixture obtained in Step (b) and Step (b') has 25% or less of Carr's Index.
The process according to claim 11 or 12, wherein the compressing in Step (c) and Step (c') is performed under a compressing pressure for providing the monolithic matrix tablet or the first layer having hardness ranging from 7 to 30 kp.
The process according to claim 12, wherein the forming a second layer is carried out by a process comprising (i') dissolving telmisartan or its pharmaceutically acceptable salt, sodium hydroxide, meglumine, and povidone in a mixed solvent of water and ethanol to prepare a binder solution; (ii') spraying the binder solution prepared in Step (i') on mannitol to prepare granules, (iii') mixing the granules prepared in Step (ii'), mannitol, and lubricant, and (iv') compressing the mixture obtained in Step (iii') on the first layer.