Carvedilol Immediate Release Formulation Having Improved Madescent

Abstract

Disclosed is an immediate-release carvedilol formulation, which is configured such that a coating layer including a polymer, wax, fatty acid and/or fatty acid ester is formed on the surface thereof. This formulation has improved madescent, and thus can exhibit high stability, in which the initial appearance of the formulation can be maintained without cracking or breaking even under storage conditions at high relative humidity.

Claims

1. An immediate-release formulation containing carvedilol as an active ingredient, wherein the formulation includes a coating layer formed on a surface thereof, and the coating layer includes at least one kind of component selected from the group consisting of polyvinyl alcohol, a polyvinyl alcohol-polyethylene glycol copolymer, a methacrylic acid-ethyl acrylate copolymer, wax, fatty acid, and fatty acid ester.

2. An immediate-release formulation containing carvedilol as an active ingredient, wherein the formulation includes a coating layer formed on a surface thereof, and the coating layer includes at least two different kinds of components selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl alcohol, a polyvinyl alcohol-polyethylene glycol copolymer, a methacrylic acid-ethyl acrylate copolymer, wax, fatty acid, and fatty acid ester.

3. The formulation of claim 2, wherein the coating layer includes any one selected from among hydroxypropyl methylcellulose and polyvinyl alcohol; and any one selected from among a polyvinyl alcohol-polyethylene glycol copolymer, a methacrylic acid-ethyl acrylate copolymer, wax, fatty acid and fatty acid ester.

4. The formulation of claim 2, wherein the coating layer includes polyvinyl alcohol and fatty acid ester; polyvinyl alcohol and a polyvinyl alcohol-polyethylene glycol copolymer; polyvinyl alcohol and a methacrylic acid-ethyl acrylate copolymer; hydroxypropyl methylcellulose and fatty acid; or hydroxypropyl methylcellulose and wax.

5. The formulation of claim 2, wherein the coating layer is used in an amount of 1 to 10 wt % based on a total weight of the formulation.

6. The formulation of claim 2, wherein the formulation includes at least one additive selected from the group consisting of a diluent, a disintegrant, a binder, and a lubricant.

7. The formulation of claim 2, wherein the formulation releases 65% or more of carvedilol within 30 min in a pH 4.5 citric acid buffer solution.

8. The formulation of claim 2, wherein the formulation prevents madescent.

Description

DESCRIPTION OF DRAWING

[0042] FIG. 1 shows the appearances of Examples and Comparative Examples under accelerated storage conditions in Test Example 2.

MODE FOR INVENTION

[0043] A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as limiting the present invention.

Comparative Examples 1 to 3

[0044] Carvedilol, crushed white sugar, mannitol, lactose hydrate, crospovidone and light anhydrous silicic acid were mixed in the amounts shown in Table 1 below and granulated with a povidone solution obtained by dissolving povidone in purified water. The granulated product was dried, tableted, mixed with crospovidone, light anhydrous silicic acid and magnesium stearate, and tableted (pressed), thus manufacturing the uncoated tablets of Comparative Examples 1 to 3. The uncoated tablet of Comparative Example 3 was additionally coated with a coating dispersion comprising hydroxypropyl methylcellulose, titanium oxide and polyethylene glycol 400 in the amounts shown in Table 1 below, thus forming a coated tablet.

TABLE-US-00001 TABLE 1 (unit: mg) Component C. Ex. 1 C. Ex. 2 C. Ex. 3 Carvedilol 12.5 12.5 12.5 Crushed white sugar 13.0 13.0 Mannitol 13.0 Lactose hydrate 64.5 64.5 64.5 Crospovidone 6.0 6.0 6.0 Light anhydrous silicic acid 2.0 2.0 2.0 Povidone 0.5 0.5 0.5 Magnesium stearate 1.5 1.5 1.5 Hydroxypropyl methylcellulose/ 3 titanium oxide/polyethylene glycol 400 (ratio: 62.5/31.2/6.3) Total weight 100 100 103

Examples 1 to 8

[0045] Coated tablets of Examples 1 to 8 were formulated by coating the uncoated tablets of Comparative Examples 1 and 2 with coating dispersions comprising the components shown in Table 2 below in the amounts corresponding to film coating rates (%).

TABLE-US-00002 TABLE 2 (unit: mg) Example 1 2 3 4 5 6 7 8 Uncoated tablet Component C. Ex. 1 C. Ex. 2 Coating Hydroxypropyl methylcellulose 65 55 dispersion Polyvinyl alcohol 48 48 37.8 42 48 37.8 Polyvinyl alcohol-polyethylene 62 62 glycol copolymer Methacrylic acid- 28 ethyl acrylate copolymer Stearic acid 10 Glycerin fatty acid ester 18 18 Wax 17 Propylene glycol fatty acid ester 18 Microcrystalline cellulose 10 Sodium lauryl sulfate 0.2 0.2 0.2 Polyethylene glycol 6000 0.2 8 8 Silicon dioxide 0.2 0.2 Titanium oxide 13.8 13.8 7.8 15 15 13.8 Talc 20 20 14 5 20 Total weight of coating dispersion 100 100 100 100 100 100 100 100 Film coating rate of coating dispersion (%) 4 6 4 8 4 5 4 10 Total weight of coated tablet 104 106 104 108 104 105 104 110

Test Example 1

[0046] The coated tablets of Examples 1 to 8, the uncoated tablets of Comparative Examples 1 and 2, and the coated tablet of Comparative Example 3 were subjected to a dissolution test at 90 rotations per min in accordance with Method 2 of the Dissolution Test of the General Test Methods in the Korean Pharmacopoeia. 30 min after initiation of the test, the release rate of carvedilol was measured at a wavelength of 285 nm using a UV absorption spectrometer. The results are shown in Table 3 below. The test solution was 1000 mL of a pH 4.5 citric acid buffer solution. [0047] Preparation of citric acid buffer solution: 138 g of citric acid and 57.5 g of sodium hydroxide were dissolved in 8 L of purified water, and the pH of the resulting solution was adjusted to pH 4.5 with about 32.5 mL of 25% hydrochloric acid, and the amount thereof was adjusted to 10 L using purified water.

TABLE-US-00003 TABLE 3 Release rate of carvedilol after 30 min (%) Ex. 1 93.73 Ex. 2 92.15 Ex. 3 93.28 Ex. 4 91.98 Ex. 5 91.96 Ex. 6 90.47 Ex. 7 90.54 Ex. 8 88.26 C. Ex. 1 94.67 C. Ex. 2 92.52 C. Ex. 3 92.85

[0048] As is apparent from Table 3, all of the coated tablets of Examples 1 to 8, the uncoated tablets of Comparative Examples and 2, and the coated tablet of Comparative Example 3 exhibited a carvedilol release rate of 65% or more within a predetermined time (30 min). Thereby, all of the coated tablets of Examples 1 to 8, the uncoated tablets of Comparative Examples 1 and 2, and the coated tablet of Comparative Example 3 were found to be formulations able to immediately release carvedilol.

Test Example 2

[0049] The coated tablets of Examples 1 to 8, the uncoated tablets of Comparative Examples 1 and 2, and the coated tablet of Comparative Example 3, none of which were packed, were stored under the following storage conditions, and the appearances thereof were observed. [0050] Storage conditions: accelerated storage conditions (402 C./relative humidity 755%)

TABLE-US-00004 TABLE 4 Initial 6 hr 5 days 27 days Ex. 1 Good Good Good Good Ex. 2 Good Good Good Good Ex. 3 Good Good Good Good Ex. 4 Good Good Good Good Ex. 5 Good Good Good Good Ex. 6 Good Good Good Good Ex. 7 Good Good Good Good Ex. 8 Good Good Good Good C. Ex. 1 Good Surface swell- Surface swell- Surface swell- ing, cracking, ing, cracking, ing, cracking, easy breaking easy breaking easy breaking C. Ex. 2 Good Surface swell- Surface swell- Surface swell- ing, cracking, ing, cracking, ing, cracking, easy breaking easy breaking easy breaking C. Ex. 3 Good Good Surface swell- Surface swell- ing, cracking, ing, cracking, easy breaking easy breaking

[0051] As shown in Table 4, when the uncoated tablets of Comparative Examples 1 and 2 were stored at high relative humidity, changes in the appearance thereof, such as surface swelling and side cracking, occurred during storage for 6 hr. As is apparent from Table 4 and FIG. 1, the coated tablet of Comparative Example 3 maintained its initial appearance for 6 hr, but the initial appearance thereof was not maintained, but side cracking occurred by the 5 days in storage.

[0052] In contrast, as shown in Table 4 and FIG. 1, the coated tablets of Examples 1 to 8 were found to maintain their initial appearances, without changes in appearance thereof, not only after storage for 5 days but also after storage for 27 days.