WO2005032553A1

WO2005032553A1 - Composition for rapidly disintegrable tablet comprising amlodipine free base

Info

Publication number: WO2005032553A1
Application number: PCT/KR2004/002574
Authority: WO
Inventors: Young Joon Park; Dae Sik Kang; Soo Yeon Joo
Original assignee: Yuhan Corporation
Priority date: 2003-10-08
Filing date: 2004-10-08
Publication date: 2005-04-14
Also published as: KR20050035907A; KR100604034B1

Abstract

The present invention relates to a composition for a rapidly disintegrable tablet comprising a therapeutically effective amount of amlodipine free base having an average particle size of 2 to 30 §, which rapidly disintegrates in the oral cavity without leaving unpleasant water-insoluble residues or generating bitter taste, and exhibits a therapeutically comparable effect to that of a general type amlodipine tablet.

Description

COMPOSITION FOR RAPIDLY DISINTEGRABLE TABLET COMPRISING AMLODIPINE FREE BASE

Field of the Invention

The present invention relates to a composition for a rapidly disintegrable tablet comprising a therapeutically effective amount of amlodipine free base.

Background of the Invention

Amlodipine, a generic name for the compound of the following formula, 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-l,4- dihydro-3,5-pyridine dicarboxylate, is a long-term calcium-channel blocker useful for treating cadiovacular diseases such as hypertension, coronary occlusion, angiospasm, and anectasis.

Korean Patent Publication No. 1995-7228 discloses pharmaceutically acceptable amlodipine acid salts, e.g., a hydrochloride, acetate, maleate, salisylate, succinate, mesylate, tosylate and besylate. Among these salts, a conventional tablet form of amlodipine besylate is marketed by Pfizer Inc. as NORVASC™ . The NORVASC™ tablet is prepared by formulating amlodipine besylate with a conventional excipient such as anhydrous calcium hydrogen phosphate and microcrystalline cellulose. However, oral intake of this tablet is not easy to those having deglutition difficulties or to patients having restricted water-intake. Accordingly, there has existed a need to develop a rapidly disintegrable type tablet, which disintegrates rapidly by the action of saliva in the oral cavity. Various methods for the preparation of a rapidly disintegrable type tablet for oral administration have been reported (see U.S. Patent Nos. 5,631,023; 5,976,577; 6,316,027; and 5,976,577 (a freeze drying or vacuum drying method); U.S. Patent Nos. 6,024,981 and 6,221,392 (a direct tableting method), and Korean Patent Application Publication No. 2001-96450 and U.S. Patent Nos. 5,466,464 and 6,048,541 (a Wow Tab or Flashdose method)). Further, Korean Laid-open Patent Publication Nos. 2001-0107754 and

2001-0006835, in particular, mention of amlodipine-containing rapidly disintegrable tablet composition, but the former gave no example for specific amlodipine tablet and the rapidly disintegrating type amlodipine tablet disclosed in the latter still exhibits poor properties.

Summary of the Invention

It is an object of the present invention to provide a composition for an amlodipine-containing rapidly disintegrable tablet, which disintegrates rapidly in the oral cavity without leaving unpleasant water-insoluble residues or generating bitter taste, and exhibits a therapeutically effect comparable to that of a general type amlodipine tablet. In accordance with the present invention, there is provided a composition for a rapidly disintegrable tablet, comprising a therapeutically effective amount of amlodipine free base having an average particle size of 2 to 30 μm.

Brief Description of the Drawings The above and other objects and features of the present invention will become apparent from the following description thereof, when taken in conjunction with the accompanying drawings which respectively show: Figs. 1 to 4 : results for the dissolution test of a rapidly disintegrable tablet prepared according to Example of the present invention and a reference tablet, in pH 1.2, pH 4.0, and pH 6.8 buffer solutions and water, respectively. Fig. 5 : results for in vivo test of a rapidly disintegrable tablet prepared according to Example 6 of the present invention and a reference tablet.

Detailed Description of the Invention The inventive rapidly disintegrable tablet composition is characterized by employing amlodipine in the form of a free base, not a salt, as an active ingredient. Amlodipine free base used in the present invention is commonly known to have a lower water-solubility, and further a lower disintegrability and bioavailability, than those of various amlodipine salts (see Korean Patent Publication No. 1995-7228, and D.M. McDaid et al., International Journal of Pharmaceutics 133, 71-83 (1996)). For example, the amlodipine besylate has a water-solubility higher than amlodipine free base by a factor of bout 59.4. Therefore, it has been recognized in the art that amlodipine free base is not suitable for use in a rapidly disintegrable tablet for oral administration. However, the use of amlodipine salts having a high water-solubility for oral administration has the problem of generating bitter taste in the oral cavity. Accordingly, the present inventors have endeavored to improve the disintegrability of amlodipine free base, and the objective has been met by controlling the particle size of the amlodipine free base. In accordance with the present invention, the amlodipine free base preferably has a particle size ranging from 2 to 30 μm. If the particle size is less than 2 μm, the amlodipine free base may dissolve in the oral cavity, leaving a bitter taste, whereas if the particle size exceeds 30 μm, the free base exhibits low disintegrability in the gastric tract. The inventive amlodipine-containing rapidly disintegrable tablet composition has such a high disintegration degree that it is easily disintegrated by the action of saliva in the oral cavity to form an emulsion which migrates into the gastric tract without the need to intake water. As used herein, the term "therapeutically effective amount" refers to the amount which produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In the present invention, amlodipine free base may be suitably used in an amount ranging from about 0.1 to 10 % by weight, preferably about 0.5 to 5 % by weight, based on the total weight of the tablet composition. The tablet composition of the present invention may further comprise an oral dissolution enhancer, which enhances the dissolution rate in the oral cavity of the tablet. The oral dissolution enhancer may be preferably a polyhydric alcohol, representative examples of which include mannitol, sorbitol, lactose, dextrose, xylitol, sucrose, glucose, dextrate, galactose, maltose, maltodextrine, levulose and erythritol. The oral dissolution enhancer may be preferably used in a spray-dried form. In addition, cellulose, microcrystalline cellulose, starch or its derivative may be used as the oral dissolution enhancer. The oral dissolution enhancer may be used in an amount ranging from about 10 to 95 % by weight, preferably about 30 to 90 % by weight, based on the total weight of the tablet composition. The inventive tablet composition may also contain one or more pharmaceutically acceptable additives. For example, a disintegrant may be used to increase the function of the oral dissolution enhancer. Representative examples of the disintegrant may include a crosslinked polyvinypyrrolidone(crospovidone), carboxymethyl cellulose calcium, crosslinked carboxymethyl cellulose sodium (croscarmellose sodium), hydroxypropyl cellulose, and sodium starch glycolate. The disintegrant may be employed in an amount ranging from about 1 to 10 % by weight based on the total weight of the tablet composition. Other components of the pharmaceutically acceptable additives may include a cellulose-based excipient for enhancing the moldability under compression of the tablet composition, e.g., a microcrystalline cellulose, starch and cellulose; an organic acid for improving the organoleptic feeling in the oral cavity, e.g., citric acid, tartaric acid and malic acid; a sweetening agent, e.g., aspartame, potassium acesulfam, sodium saccharin, ammonium glycyrrhizinate; a flavor; and a pigment. The cellulose compound may be used in an amount ranging from about 1 to 30 % by weight based on the total weight of the tablet composition, and the organic acid, sweetening agent, flavor or pigment may be used in amount ranging from about 0.5 to 5 % by weight based on the total weight of the tablet composition. Further, other conventional, pharmaceutically acceptable additives may be also used in the present invention, including but not limited to: lubricants such as silicon dioxide, colloidal silicon dioxide, magnesium stearate, talc, magnesium trisilicate, sodium stearyl fumarate, stearic acid and polyethylene glycol; surfactants for increasing the water-solubility and disintegrability of the drug such as non-ionicl sufactant (e.g., polysorbates) and ionic surfactants (e.g., sodium lauryl sulfate); and sucrose esters, each of which may be employed in an amount ranging from about 0.5 to 5 % by weight based on the total weight of the tablet composition. The inventive composition may be formed into a tablet using a conventional manner, e.g., by a direct tableting method, or a granulating and tableting method. The Examples and Test Examples are given for the purpose of illustration only, and are not intended to limit the scope of the invention. Example 1

The ingredients shown in Table 1, except for magnesium stearate and magnesium trisilicate, were mixed and passed through a 20-mesh sieve (U.S. standard sieve) to obtain a powder mixture. Magnesium stearate and magnesium trisilicate were passed through a 40-mesh sieve (U.S. standard sieve) and then combined with the powder mixture obtained in the above. The resulting mixture was compressed to obtain a rapidly disintegrable 150 mg tablet (Hardness: about 4 - 5 Kp).

Table 1

Example 2

The ingredients shown in Table 2, except for magnesium stearate and magnesium trisilicate, were mixed and passed through a 20-mesh sieve (U.S. standard sieve) to obtain a powder mixture. Magnesium stearate and magnesium trisilicate were passed through a 40-mesh sieve (U.S. standard sieve) and then combined with the powder mixture obtained in the above. The resulting mixture was compressed to obtain a rapidly disintegrable 150 mg tablet (Hardness: about 3 ~ 4 Kp). Table 2

Example 3

The ingredients shown in Table 3 were passed through a 20-mesh sieve (U.S. standard sieve) and mixed for 5 minutes. The powder mixture was compressed with a pressure of 90 kgf/cnf by a roll compactor to obtain a granule. The resulting granule was passed through a 20-mesh sieve (U.S. standard sieve) and then compressed to obtain a rapidly disintegrable 200mg tablet (Hardness: about 4 ~ 5 Kp).

Table 3

Example 4

The ingredients shown in Table 4, except for magnesium stearate and magnesium trisilicate, were mixed and passed through a 20-mesh sieve (U.S. standard sieve). The resulting mixture was granulated, using purified water, with a high-speed granulator. The granule was dried in 70 ^°C and passed through a 25 -mesh sieve (U.S. standard sieve). Magnesium stearate and magnesium trisilicate were passed through a 40-mesh sieve (U.S. standard sieve) and then combined with the granule obtained in the above. The resulting mixture was compressed to obtain a rapidly disintegrable 250mg tablet (Hardness: about 5 - 6 Kp). Table 4

Example 5

The ingredients shown in Table 5, except for magnesium stearate and magnesium trisilicate, were mixed and passed through a 20-mesh sieve (U.S. standard sieve). The resulting mixture was granulated, using purified water, with a fluid bed granulator at 80 ^°C . The resulting granule was passed through a 20-mesh sieve (U.S. standard sieve). Magnesium stearate and magnesium trisilicate were passed through a 40-mesh sieve (U.S. standard sieve) and then combined with the granule obtained in the above. The resulting mixture was compressed to obtain a rapidly disintegrable 300 mg tablet (Hardness: about 6 - 7 Kp). Table 5

Example 6

Referring to the ingredients shown in Table 6, amlodipine, spray-dried lactose and citric acid were mixed and passed through a 20-mesh sieve (U.S. standard sieve), and the resulting powder mixture was granulated using purified water with a high-speed granulator. The granule was dried at 80 °C and passed through a 30mesh sieve (U.S. standard sieve). The remaining ingredients excluding magnesium stearate, magnesium trisilicate and stearic acid were passed through a 20-mesh sieve (U.S. standard sieve) and then combined with the granule obtained in the above. Magnesium stearate, magnesium trisilicate and stearic acid were passed through a 40-mesh sieve (U.S. standard sieve) and then combined with the mixture obtained in the above. The resulting mixture was compressed to obtain a rapidly disintegrable 150 mg tablet (Hardness: about 3 - 4 Kp). Table 6

Comparative Example 1

The same procedure as described in Example 1 was repeated except that the ingredients shown in Table 7 were employed to obtain a rapidly disintegrable 150 mg tablet (Hardness: about 4 - 5 Kp).

Table 7

Comparative Example 2 The same procedure as described in Example 2 was repeated except that the ingredients shown in Table 8 were employed to obtain a rapidly disintegrable 150 mg tablet (Hardness: about 3 - 4 Kp). Table 8

Comparative Example 3

The same procedure as described in Example 3 was repeated except that the ingredients shown in Table 9 were employed to obtain a rapidly disintegrable 150 mg tablet (Hardness: about 3 - 4 Kp).

Table 9

Comparative Example 4

The same procedure as described in Example 4 was repeated except that the ingredients shown in Table 10 were employed to obtain a rapidly disintegrable 250 mg tablet (Hardness: about 5 - 6 Kp). Table 10

Comparative Example 5 The same procedure as described in Example 5 was repeated except that the ingredients shown in Table 11 were employed to obtain a rapidly disintegrable 300 mg tablet (Hardness: about 6 - 7 Kp).

Table 11

Comparative Example 6

The same procedure as described in Example 6 was repeated except that the ingredients shown in Table 12 were employed to obtain a rapidly disintegrable 150 mg tablet (Hardness: about 3 - 4 Kp).

Table 12

Test Example 1

The hardness, the disintegration time in the oral cavity and the extent of the taste masking for the tablets obtained in Examples 1 - 6 and Comparative Examples 1 - 6 were measured by the following methods. The measurement results are shown in Table 13. (1) Hardness

The hardness of each tablet was measured with a tablet hardness tester (Schleuniger-2E, Dr. K. Schleuniger & Co.). The test was repeated 3- 10 times for each sample and the results were averaged.

(2) Disintegration time

The time for a sample to completely disintegrate by the action of saliva in the oral cavity was measured employing six male adults. The test was duplicated three times and the results were averaged.

(3) Organoleptic test

The organoleptic test was conducted according to the cross-over method, which is carried out in double blinded at random, employing six male adults.

Table 13

(The mark * is directly proportional to unpleasant bitter taste.)

Table 13 shows that there are no significant differences in the disintegration time between the tablets of Examples 1 - 6 and those of Comparative Examples 1 - 6, and in case of the tablets of Examples 1 - 6, bitter taste of the active ingredients was effectively masked. Test Example 2

Comparative dissolution tests between the tablet prepared in Example 6 (hereinafter "Test tablet") and a commercially available tablet containing Amlodipine besylate (Norvasc^® 5mg, PFIZER; hereinafter "Reference tablet") were carried out in water or buffer solutions of pH 1.2, pH 4.0 and pH 6.8, respectively (50rpm, 900ml). The results are shown in Figs. 1 to 4 (Fig. 1 : dissolution in a pH 1.2 buffer solution, Fig. 2: dissolution in a pH 4.0 buffer solution, Fig. 3: dissolution in a pH 6.8 buffer solution, and Fig. 4: dissolution in water). As shown in Figs. 1 to 4, there is no significant difference in dissolution time between two tablets.

Test Example 3

The bioequivalence test was carried out for Test tablet (Example 6) and

Reference tablet (Norvasc 5mg, PFIZER ) using beagle dogs under fast. The test was carried out according to the cross-over method. That is, after cross- administration of Test tablet and Reference tablet to the test dogs, blood samples were taken at present times and the drug concentrations were measured. The concentration profile of amlodipine for each tablet is shown in Fig. 5 which illustrates that Test tablet is biologically equivalent to Reference tablet. While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made by those skilled in the art, which also fall within the scope of the invention as defined by the appended claims.

Claims

What is claimed is:

1. A composition for a rapidly disintegrable tablet, comprising a therapeutically effective amount of amlodipine free base having an average particle size of 2 to 30 μm.

2. The composition of claim 1, wherein the amount of amlodipine free base is in the range of 0.1 to 10 % by weight, based on total weight of the composition.

3. The composition of claim 1, further comprising an oral dissolution enhancer.

4. The composition of claim 3, wherein the oral dissolution enhancer is selected from the group consisting of mannitol, sorbitol, lactose, dextrose, xylitol, sucrose, glucose, dextrate, galactose, maltose, maltodextrine, levulose, erythritol, cellulose, microcrystalline cellulose, starch or its derivative, and a mixture thereof.

5. The composition of claim 3, wherein the oral dissolution enhancer is employed in an amount ranging from about 10 to 95 % by weight, based on the total weight of the composition.

6. The composition of claim 1 or 3, further comprising at least one pharmaceutically acceptable additive selected from the group consisting of a disintegrant, cellulose-based expient, sweetening agent, organic acid, lubricant, flavor, pigment, surfactant, and a mixture thereof.

7. The composition of claim 6, wherein the disintegrant is selected from the group consisting of a crosslinked polyvinylpyrrolidone, calcium carboxymethyl cellulose, crosslinked carboxymethyl cellulose sodium, hydroxypropyl cellulose, sodium starch glycolate, and a mixture thereof.

8. The composition of claim 6, wherein the cellulose-based excipient is selected from the group consisting of a microcrystalline cellulose, starch, cellulose, and a mixture thereof.

9. The composition of claim 6, wherein the sweetening agent is selected from the group consisting of aspartame, potassium acesulfam, sodium saccharin, ammonium glycyrrhizinate, and a mixture thereof.

10. A rapidly disintegrable tablet containing amlodipine free base, prepared by tableting the composition according to any one of claims 1 to 9.