WO2005123041A1

WO2005123041A1 - Oral dispersible tablet composition of amoxycillin and/or clavulanic acid comprising a surface-modified sodium bicarbonate

Info

Publication number: WO2005123041A1
Application number: PCT/KR2005/001872
Authority: WO
Inventors: Young Joon Park; So Yun Lee
Original assignee: Yuhan Corporation
Priority date: 2004-06-18
Filing date: 2005-06-17
Publication date: 2005-12-29
Also published as: KR100676617B1; KR20060046470A; CN1968682A

Abstract

An oral dispersible tablet composition comprising amoxycillin, or a combination of amoxycillin and clavulanic acid or a salt thereof as an active ingredient together with a surface-modified sodium bicarbonate exhibits improved storage stability and undergoes spontaneous disintegration on contact with water.

Description

ORAL DISPERSIBLE TABLET COMPOSITION OF AMOXYCILLIN AND/OR CLAVϋLANIC ACID COMPRISING A SURFACE-MODΓFIED SODIUM BICARBONATE

FTFJ.D OF THE INVENTION

The present invention relates to an oral dispersible tablet composition comprising amoxycillin, or a combination of amoxycillin and clavulanic acid or a salt thereof as an active ingredient together with a surface-modified sodium bicarbonate, which exhibits improved storage stability and undergoes rapid spontaneous disintegration on contact with water.

BACKGROTTNP OF THE INVENTION Amoxycillin, a penicillin-based antibitic, is a well known and widely used oral medicament for bacterial infections. For the purpose of preventing in vivo decomposition of amoxycillin by enzyme, a combination of amoxycillin and a beta-lactamase inhibitor, clavulanic acid or a salt thereof is recently widely employed, marketed by GlaxoSmithKline under the trade mark of Augmentin™. Clavulanic acid or its salt, however, is extremely hygroscopic, and a conventional formulation containing it is prone to undergo degradation through absorption of ambient moisture during storage. In particular, when a dry syrup preparation comprising clavulanic acid or its salt is suspended in water, the resultant suspension is subject to abrupt degradation at room temperature. Accordingly, there have been reported various studies to develop formulations containing amoxycillin and clavulanic acid or its salt in the form of a dispersible tablet. For example, PCT International Publication No. WO 92/19227 discloses dispersible tablet formulations of amoxycillin and potassium clavulanate comprising compacted granules including intra-granular and extra-granular disintegrants. However, the tablets do not undergo satisfactorily spontaneous disintegration on contact with water. Also, PCT International Publication No. WO 91/15197 discloses an effervescent tablet formulation of amoxycillin and clavulanic acid which contains an effervescent acid-alkali carbonate couple which generates carbon dioxide on contact with water. However, the solution induced from the effervescent tablet is undesirably stimulating in the mouth due to excessive bubbling. In addition, the effervescent tablet is very sensitive to moisture, causing gradual disintegration during storage.

SUMMARY OF THE INVENTION

It is, therefore, a primary object of the present invention to provide a dispersible tablet composition of amoxycillin, or amoxycillin and clavulanic acid or a salt thereof for oral administration having improved storage stability and spontaneous disintegratability on contact with water. In accordance with one aspect of the present invention, there is provided an oral dispersible tablet composition comprising amoxycillin, or a combination of amoxycillin and clavulanic acid or a salt thereof as an active ingredient; a surface-modified sodium bicarbonate; and a pharmaceutically acceptable additive.

DETAΠ ED DESCRIPTION OF THE TI ENTTON

Throughout this specification, the term "spontaneous disintegration" means that when a tablet sample is dropped to a small amount, e.g., about 5 ml, of water, it voluntarily disintegrates and forms a dispersion suitable for oral administration within a short time, e.g., 60 seconds, in the absence of any applied external physical power such as stirring. In addition, throughout this specification, sodium bicarbonate of which the surface is processed with sodium carbonate is designated as "a surface-modified sodium bicarbonate". Such a surface-modified sodium bicarbonate is commercially available, and preferably consists of about 88% by weight of sodium bicarbonate and about 12% by weight of sodium carbonate. The inventive composition for a dispersible tablet comprises as an active ingredient amoxycillin, or a combination of amoxycnlin and clavulanic acid or a salt thereof, preferably the combination of amoxycillin and clavulanic acid or a salt thereof, more preferably a combination of amoxycillin trihydrate and potassium clavulanate. In case of the combination, amoxycillin and clavulanic acid or the salt thereof may be combined in a weight ratio of 1:1 to 30:1, and the amount of the active ingredient may be in the range of 10 to 60% by weight based on the total amount of the composition. The inventive composition comprises a surface-modified sodium bicarbonate which acts to stabilize the hygroscopic active ingredient as well as to accelerate the disintegration of dispersible tablets. More particularly, sodium carbonate on the surface of the surface-modified sodium bicarbonate functions to absorb the moisture present in air and the formulation itself to form very stable sodium sesquicarbonate which is very effective in preventing the degradation of the active ingredient during storage. La addition, the surface-modified sodium bicarbonate is capable of generating carbon dioxide on contact with water, thereby helping voluntary breakdown and dispersion of the tablet. The surface-modified sodium bicarbonate may be used in an amount ranging from 0.1 to 10% by weight, preferably from 0.5 to 2% by weight based on the total amount of the composition. The inventive composition further comprises a pharmaceutically acceptable additive for oral administration such as a diluent, disintegrant, organic acid, aromatic, sweetener and lubricant. Representative examples of the diluent that may be used in the present invention include microcrystalline cellulose, lactose, sugar, dextrose, mannitol, xylitol, sorbitol, maltitol, lactitol and a mixture thereof, and a spray-dried material thereof, wherein microcrystalline cellulose is preferred due to its good wetting and swelling properties which make the disintegration of the tablet easier. Suitable disintegrant that may be used in the present invention is crospovidone, sodium starch glycolate, croscarmellose sodium, starch, pregelatinized starch, low substituted hydroxypropyl cellulose or a mixture thereof. In the present invention, the disintegrant acts to enhance dispersion property of disintegrated tablet particles in water. Representative examples of the organic acid that may be used in the present invention include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid and a mixture thereof, wherein preferred is succinic acid which is non-hygroscopic and does not interact with the active ingredient. Further, the inventive composition may comprise the sweetener such as aspartame, water-soluble sugars and polyols. The composition of the present invention comprising said components may be formulated into a dispersible tablet in accordance with the conventional method, e.g., a direct compression method and dry granulation/compression method. In the present invention, the dispersible tablet may be prepared so as to have a higher hardness as compared to the conventional dispersible tablet because such a hard tablet of the present invention exhibits no decrease in spontaneous disintegration property on contact with water. As described above, the inventive composition of amoxycillin, or amoxycillin and clavulanic acid or a salt thereof comprising a surface-modified sodium bicarbonate can be used in manufacturing a dispersible tablet which exhibits improved storage stability and spontaneously disintegrates within 60 seconds on contacting water to form a suspension suitable for oral administration. The following Examples are intended to further illustrate the present invention without limiting its scope.

F.xamplfts 1 to 7

The constituents shown in Table 1 were mixed to obtain various compositions, and each composition was compressed into a dispersible tablet having a hardness of 6 to 9 kp by the conventional direct compression method. Table 1

note : commercially available from SPI Pharma

Examples 8 to 12

The "as granule" constituents shown in Table 2 were mixed, compacted with a roller compactor and granulated. The granules thus obtained and "extra granule" constituents shown in Table 2 were mixed and then the mixture was compressed into a dispersible tablet having a hardness of 6 to 9 kp by the conventional dry granulation/compression method. Table 2

* note : commercially available from SPI Pharma

Comparative Examples 1 to 7

The "as granule" constituents shown in Table 3 were mixed, compacted with a roller compactor and granulated. The granules thus obtained and "extra granule" constituents shown in Table 3 were mixed and then the mixture was compressed into a dispersible tablet having a hardness of 6 to 9 kp by the conventional dry granulation/compression method. Table 3

Comparative Examples 8 and Q

The "as granule" constituents shown in Table 4 were mixed, compacted with a roller compactor and granulated. The granules thus obtained and "extra granule" constituents shown in Table 4 were mixed and then the mixture was compressed into a dispersible tablet having a hardness of 6 to 9 kp by the conventional dry granulation/compression method.

The dispersible tablets manufactured in Examples and Comparative Examples were examined for the following properties.

(1) Hardness The hardness (kp) of a dispersible tablet was measured using a hardness measuring mstrument which is commercially available from Dr. K. Schleuniger & Co.

(2) Friability Friability of a dispersible tablet was calculated from the change in the weight before and after a test with a friability measuring mstrument which is commercially available from Fine Scientific Co.

(3) Wetting Rate The wetting rate (sec) of a dispersible tablet was determined by dropping it to 10ml of distilled water (in a vessel having a diameter of 10cm) maintained at room temperature and then measuring the time for water to reach the center of the tablet.

(4) Disintegration Rate The disintegration rate (sec) of a dispersible tablet was determined by dropping it to 5ml of distilled water (in a spoon) maintained at room temperature and then measuring the time for it to become completely disintegrated.

(5) Content The content (%) of the active ingredient in a dispersible tablet was analyzed by HPLC based an Antibiotic Pharmaceutical Titer Test method.

(6) pH 5 dispersible tablets were suspended in 25 ml of distilled water, if necessary with stirring, and the pH of the resultant suspension was measured.

(7) Taste A dispersible tablet was suspended in 5 ml of distilled water, if necessary with stirring, and the overall taste and flavor of the resultant suspension was determined as either "O" or "X" by 5 adult women.

Test Example 1

The wetting and disintegration rates, and the pH and overall taste of the suspension obtained therefrom were determined for the inventive dispersible tablets of Examples 1 to 12; the dispersible tablets of Comparative Examples 1 to 8; and Augmentin™ dry syrup (GlaxoSnnmKline), as described above.

The results are shown in Table 5. 10

Table 5

* note : do not disperse spontaneously without stirring and remains only swollen state As can be seen in Table 5, the tablets of Examples 1 to 12 underwent complete and voluntary disintegration within 60 seconds on contacting water, and the resultant suspensions had satisfactory tastes and flavors appropriate for oral administration. In contrast, the tablets of Comparative Examples 1 to 7 did not disintegrate and maintained their appearances of a swollen form in water without stirring. As to the tablet of Comparative Example 8 which is an effervescent tablet containing large amounts of acid and alkaline components, excessive generation of carbon dioxide in water was observed and the suspension obtained therefrom was very irritating, not appropriate for oral administration.

Test Example 2 hi order to investigate the storage stability of the dispersible tablets of

Example 8 and Comparative Example 9, the tablet was packaged in an aluminum bag and kept under an accelerated storage condition of 40 ^°C and

75% relative humidity. The changes in the tablet and the suspension obtained therefrom were measured in terms of the contents of amoxycillin trihydrate and potassium clavulanate, hardness, friability and pH after 0, 2, 4 and 6 months. The results are shown in Table 6.

12

Table 6

As ^• shown in Table 6, the tablet of Example 8 shows remarkably improved storage stability even under the condition of high temperature and humidity as compared with that of Comparative Example 9. In particular, as for the content of potassium clavulanate, the inventive tablet shows about 5% weight loss, while the comparative one, about 11% weight loss. Thus, the inventive composition can be advantageously used for a dispersible tablet which exhibits improved storage stability and spontaneously disintegrates within 60 seconds on contacting water to form a suspension suitable for oral administration. 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 to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

WHAT TS CLAIMED TS;

1. An oral dispersible tablet composition comprising amoxycillin, or a combination of amoxycillin and clavulanic acid or a salt thereof as an active ingredient; a surface-modified sodium bicarbonate; and a pharmaceutically acceptable additive.

2. The oral dispersible tablet composition of claim 1, wherein the amoxycillin is amoxycillin trihydrate.

3. The oral dispersible tablet composition of claim 1, wherein the salt of clavulanic acid is potassium clavulanate.

4. The oral dispersible tablet composition of claim 1, wherein the weight ratio of amoxycillin and clavulanic acid or the salt thereof is in the range of

1:1 to 30:1,

5. The oral dispersible tablet composition of claim 1, wherein the amount of the active ingredient is in the range of 10 to 60% by weight based on the total amount of the composition.

6. The oral dispersible tablet composition of claim 1, wherein the amount of the surface-modified sodium bicarbonate is in the range of 0.1 to 10% by weight based on the total amount of the composition.

7. The oral dispersible tablet composition of claim 1, wherein the pharmaceutically acceptable additive is a diluent, disintegrant, organic acid, aromatic, sweetener or lubricant.

8. The oral dispersible tablet composition of claim 7, wherein the diluent is selected from the group consisting of microcrystalline cellulose, lactose, sugar, dextrose, mannitol, xylitol, sorbitol, maltitol, lactitol and a mixture thereof, and a spray-dried material thereof.

9. The oral dispersible tablet composition of claim 7, wherein the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, starch, pregelatinized starch, low substituted hydroxypropyl cellulose and a mixture thereof.

10. The oral dispersible tablet composition of claim 7, wherein the organic acid is succinic acid.

11. A dispersible tablet prepared by tableting the composition of any one of claims 1 to 10.

12. The dispersible tablet of claim 11 which undergoes spontaneous disintegration within 60 seconds on contact with water to form a suspension.