EP1067937A1

EP1067937A1 - Sustained-release composition containing cefaclor

Info

Publication number: EP1067937A1
Application number: EP99912140A
Authority: EP
Inventors: Hyun Soo Kim; Young Joon Park
Original assignee: Yuhan Corp
Current assignee: Yuhan Corp
Priority date: 1998-04-01
Filing date: 1999-04-01
Publication date: 2001-01-17
Also published as: WO1999049868A1; AU3057299A; KR19990079034A; CN1151791C; KR100296413B1; CN1303291A; JP2002509887A

Abstract

A composition comprising 30 to 90 wt.% of cefaclor, 5 to 60 wt.% of a hydroswelling polymer and 1 and to 10 wt.% of salt based on the total weight of the composition releases cefaclor in the gastric fluid in a steady sustained manner over a period over 20 hours.

Description

- 1 -

SUSTAINED-RELEASE COMPOSITION CONTAINING CEFACLOR

Field of the Invention

The present invention relates to a novel sustained- release composition containing cefaclor.

Description of the prior Art

Cefaclor, an orally administrable cephalosporin antibiotic, is stable in an acidic environment of pH 4.5 or below and it is absorbable mainly at the upper gastrointestinal tract. An ordinary cefaclor formulation is administered at least three times a day, because the half life of cefaclor in serum is relatively short, i.e., less than an hour. Accordingly, many attempts have been made to develop a novel formulation which can release cefaclor in a sustained manner over a prolonged period of time. United States Patent No. 4,713,247 discloses a long- acting formulation of cefaclor which is being marketed by Shionogi & Co., Ltd. of Japan under a trade name of L- KEFRAL^Θ. The above formulation is in the form of a capsule comprising a mixture of a rapid-release component and a slow-release component at a ratio of about 4:6, wherein the rapid-release component releases cefaclor in the gastric fluid while the slow-release component dissolves at the intestine, thereby enabling oral administration thereof twice a day. United States Patent No. 4,968,508 describes a formulation for sustained drug delivery comprising cefaclor, a hydrophilic polymer and an enteric polymer such as an acrylic polymer. This formulation, available under a trade name of Ceclor(CD)^® from Eli Lilly & Co., Ltd. of United States, releases cefaclor at a constant rate while it passes through the stomach and small intestine.

Although the above formulations release cefaclor in a - 2 - sustained manner, they still need to be administered at least twice a day. Further, they often release significant portions of the active ingredient at the lower part of the intestines where cefaclor absorption does not take places. Furthermore, since the conventional sustained release formulation has been designed to release cefaclor only at a constant rate, in order to be taken once a day, a large amount of cefaclor should be used, and thus, it may cause undesired side effects due to excessive initial drug serum concentrations.

Therefore, there still exists needs to develop a more effective cefaclor delivery system.

Summary of the Invention

Accordingly, it is a primary object of the present invention to provide a novel sustained-release composition containing cefaclor.

In accordance with the present invention, there is provided a sustained-release composition comprising 30 to 90 wt% of cefaclor, 5 to 60 wt% of a hydroswelling polymer and 1 to 10 wt% of a salt based on the total weight of the composition, said salt being capable of releasing gaseous C0₂ in a gastric environment. The present invention provides the sustained release formulations which can be administered once a day as well as twice a day.

Brief Description of the Drawing

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 drawing wherein:

Fig. 1 shows the time-dependent cefaclor concentration in the blood of dogs administered with the formulation of the present invention (♦) and a commercially available cefaclor capsule (D), respectively. - 3 -

Detailed Description of the nvent.inn

The composition of the present invention is capable of delivering cefaclor in the gastric fluid, continuously in a controlled manner over a period of about 24 hours. This capability arises from the combined use of a hydroswelling polymer matrix and a foaming agent that generates gaseous C0₂ when it contacts the acidic gastric fluid. Namely, when the inventive composition enters the stomach, it swells and becomes buoyant due to foaming. The swollen, foamed composition then floats to the upper layer of the gastric fluid and remains afloat there for a long period of time while releasing cefaclor steadily through the swollen hydroswelling polymer matrix. The amount of cefaclor in the sustained-release composition of the present invention is in the range of from 30 to 90wt%, preferably 60 to 90wt%, based on the total weight of the composition.

The composition of the present invention contains a hydroswelling polymer that is capable of swelling in a gastric environment. Representative hydroswelling polymers that can be used in the inventive composition include hydroxypropylcellulose ( HPC ) , hydroxypropylmethyl- celluose ( HPMC ) , sodium carboxymethylcellulose , polyvinylpyrrolidone, sodium alginate, and a mixture thereof, among which hydroxypropylmethylcelluose (HPMC) and sodium carboxymethylcellulose are preferred. Such a hydroswelling polymer is present in the sustained-release composition of the present invention in an amount of 5 to 60 wt% based on the total weight of the composition. By adjusting the content of this hydroswelling polymer, the cefaclor release rate of the inventive composition in gastrointestinal fluids can be controlled. As the content of the hydroswelling polymer increases, the release rate of the cefaclor decreases.

The composition of the present invention further contains a carbonate or bicarbonate salts, as a foaming - 4 - agent which can generate gaseous C0₂ on contacting the gastric fluid. Examples of such salts are sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium sesquicarbonate, and a mixture thereof, wherein sodium bicarbonate is preferred. The foaming agent may be used in an amount ranging from 1 to 10 wt%, preferably from 1 to 5 wt% based on the total weight of the composition. The use of an excessive amount of sodium bicarbonate would generate excessive amount of C0₂ gas, thereby irritating the stomach, disintegrating the formulation, and losing the sustained release characteristic .

The composition of the present invention may further contain an organic acid such as citric acid, tartaric acid, maleic acid and a mixture thereof in an amount ranging from 1 to 10wt% based on the total weight of the composition. The organic acid acts as a pH buffer. That is, the organic acid can prevent temporary pH increase in gastric juice caused by ingestion of foods. The composition of the present invention may also contain a foaming buffer such as calcium carbonate, magnesium carbonate and a mixture thereof in an amount ranging from 1 to 10wt% based on the total weight of the composition. The foaming buffer prevents excessive production of C0₂ gas .

The cefaclor containing composition of the present invention may be formulated in a conventional manner, if desired, with other pharmaceutical excipients and/or carriers, into a tablet or a pellet. The pharmaceutically acceptable excipients may include: microcrystalline cellulose, pectin, sodium alginate, chitosan, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethyl-cellulose acetate succinate, cellulose acetate trimelitate, gelatin, sucrose, lactose, mannitol, ethylcellulose, magnesium aluminium silicate and natural, or partially or totally synthetic hydrophilic gums, and the like. - 5 -

The cefaclor containing formulation of the present invention may be prepared in accordance with the procedure described below.

First, cefaclor and a hydroswelling polymer are mixed with a foaming agent and the resulting mixture is granulated in a conventional wet process. The granules thus obtained are mixed with a lubricant and the resulting mixture is formulated into tablets by a conventional process. The lubricant which can be used in the present invention includes stearic acid, magnesium stearate, colloidal silicon dioxide, and the like.

Preferably, in order to minimize the initial floating time and thereby to release cefaclor from the floated formulation in a sustained manner, cefaclor and an excipient are mixed together with portions of the hydroswelling polymer and foaming agent and the mixture is granulated in accordance with a conventional wet process. Then, the granules are mixed with remaining portions of the hydroswelling polymer and foaming agent, and a lubricant is added thereto. Subsequently, the resulting mixture is formulated into tablets.

In this method, the organic acid may be added in the first step and the foaming buffer may be added in both steps. Further, the granules contain the foaming agent in an amount ranging from 10 to 90wt%, preferably 50 to 90wt% based on the total weight of the foaming agent used.

The inventive formulation thus prepared releases cefaclor in a controlled steady manner over a prolonged period of time, e.g., over 20 hours and may be administered once a day, as well as twice a day depending on the release rate.

The following Examples and Test are intended to illustrate the present invention more specifically, without limiting the scope of the invention. 6 -

Example 1

400g of cefaclor was mixed with 20g of hydroxypropylmethylcellulose, 20g of calcium carbonate, lOg of sodium bicarbonate, lOg of citric acid, lOg of hydroxypropylmethylcellulose phthalate and 2g of colloidal silicon dioxide. The mixture was granulated using 140ml of 70% ethanol, and the granules were dried at 40 °C to a moisture content of below 3%, before passing through No. 20 mesh.

The granules thus obtained were mixed with 60g of hydroxypropylmethylcellulose, 20g of calcium carbonate, 5g of sodium bicarbonate and 30g of sodium carboxymethyl- cellulose. Added thereto were lg of colloidal silicon dioxide and 3g of magnesium stearate which had previously been passed through No. 40 mesh. The resulting mixture was formed into tablets by using a conventional press-tableting machine.

When the tablet thus obtained was added to an artificial gastric fluid, it floated to the upper layer and remained afloat for over 6 hours.

The dissolution rate of cefaclor from the tablet was measured according to dissolution test method II as set forth in the Korean Pharmacopeia under the condition of adding the tablet to 900ml of 0.1N HCl aqueous solution at

37 °C. The results are shown in Table I.

Table I

Time (min) Cumulative Dissolution rate(%)

15 • 18.03

30 25.58

60 37.17

120 59.52

240 91.24

480 100.0 - 7 -

Example 2

393g of cefaclor was mixed with 20g of hydroxypropylmethylcellulose, 20g of calcium carbonate, lOg of sodium bicarbonate, lOg of citric acid and lOg of hydroxypropylmethylcellulose phthalate. The mixture was granulated using 140ml of 70% ethanol, and the granules were dried at 40°C to a moisture content of below 3%, before passing through No. 20 mesh. The granules thus obtained were mixed with 80g of hydroxypropylmethylcellulose, 20g of calcium carbonate, 5g of sodium bicarbonate and 25g of microcrystalline cellulose. Added thereto were 6g of magnesium stearate which had previously been sieved through No. 40 mesh. The resulting mixture was formed into tablets by using a conventional press-tableting machine.

When the tablet thus obtained was added to an artificial gastric fluid, it floated to the upper layer and remained afloat for over 6 hours. The dissolution rate of cefaclor was measured as in Example 1 and the results are shown in Table II.

Table II

Time (min) Cumulative Dissolution rate(%)

15 8.61

30 14.30

60 23.95

120 41.93

240 71.29

360 94.96 - 8 -

Example 3

393g of cefaclor was mixed with 20g of hydroxypropylmethylcellulose, 20g of calcium carbonate, lOg of sodium bicarbonate and lOg of citric acid. • The mixture was granulated using 120ml of 95% ethanol containing lOg of hydroxypropylmethylcellulose phthalate, and the granules were dried at 40 °C to a moisture content of below 3%, before passing through No. 20 mesh. The granules thus obtained were mixed with 70g of hydroxypropylmethylcellulose, 15g of calcium carbonate, 15g of sodium bicarbonate and 31g of microcrystalline cellulose. Added thereto were 3g of colloidal silicon dioxide and 3g of magnesium stearate which had previously been sieved through No. 40 mesh. The resulting mixture was formed into tablets by using a conventional press-tableting machine.

When the tablet thus obtained was added to an artificial gastric fluid, it floated to the upper layer within 30 seconds and remained afloat for over 6 hours. The dissolution rate of cefaclor was measured as in Example 1 and the results are shown in Table III.

Table III

Time (min) Cumulative Dissolution rate(%)

15 15.44

30 22.37

60 35.13

120 60.35

240 90.40

360 100.0 - 9 -

Example 4

400g of cefaclor was mixed with 20g of hydroxypropylmethylcellulose, 20g of calcium carbonate, lOg of sodium bicarbonate, lOg of citric acid and lg of colloidal silicon dioxide. The mixture was granulated using 120ml of 95% ethanol containing lOg of hydroxypropylmethylcellulose phthalate, and the granules were dried at 40 °C to a moisture content of below 3%, and then, passed through No. 20 mesh.

The granules thus obtained were mixed with 70g of hydroxypropylmethylcellulose, 20g of calcium carbonate, 5g of sodium bicarbonate and 40g of microcrystalline cellulose. Added thereto were 2g of colloidal silicon dioxide and 3g of magnesium stearate which had previously been sieved through No. 40 mesh. The resulting mixture was formed into tablets by using a conventional press-tableting machine.

When the tablet thus obtained was added to an artificial gastric fluid, it floated within 30 seconds to the upper layer and remained afloat for over 5 hours.

The dissolution rate of cefaclor was measured as in Example 1 and the results are shown in Table IV.

Table IV

Time (min) Cumulative Dissolution rate(%)

15 4.33

30 10.58

60 25.93

120 52.33

240 100.0

Example 5

393g of cefaclor was mixed with llOg of hydroxypropylmethylcellulose, 20g of calcium carbonate, lOg of sodium bicarbonate and lOg of citric acid. The mixture was - 10 - granulated using 160ml of 70% ethanol containing 10g of hydroxypropylmethylcellulose phthalate, and the granules were dried at 35°C to a moisture content of below 3%, and then, passed through No. 20 mesh.

The granules thus obtained were mixed with lOg of hydroxypropylmethylcellulose, 2g of sodium bicarbonate and 43g of macrocrystalline cellulose. Added thereto were 3g of colloidal silicon dioxide and 6g of magnesium stearate which had previously been sieved through No. 40 mesh. The resulting mixture was formed into tablets by using a conventional press-tableting machine.

When the tablet thus obtained was added to an artificial gastric fluid, it floated within 30 seconds to the upper layer and remained afloat for over 10 hours.

The dissolution rate of cefaclor was measured as in Example 1 and the results are shown in Table V.

Table V

Time (min) Cumulative Dissolution rate(%)

15 3.29

30 6.53

60 12.93

120 24.67

240 47.50

360 64.23

480 88.56

600 100.0

Example 6

393g of cefaclor was mixed with 20g of hydroxypropylmethylcellulose, 20g of calcium carbonate, lOg of sodium bicarbonate and lOg of citric acid. The mixture was granulated using 140ml of 95% ethanol containing lOg of - 11 hydroxypropylmethylcellulose phthalate, and; the granules were dried at 40 °C to a moisture content of below 3%, and then, passed through No. 20 mesh.

The granules thus obtained were mixed with 60g of hydroxypropylmethylcellulose, lOg of sodium bicarbonate, 20g of calcium carbonate and 31g of microcrystalline cellulose. Added thereto were 3g of colloidal silicon dioxide and 3g of magnesium stearate which had previously been sieved through No. 40 mesh. The resulting mixture was formed into tablets by using a conventional press-tableting machine.

When the tablet thus obtained was added to an artificial gastric fluid, it floated within 30 seconds to the upper layer and remained afloat for over 6 hours.

The dissolution rate of cefaclor was measured as in Example 1 and the results are shown in Table VI.

Table VI

Time (min) Cumulative Dissolution rate(%)

15 6.30

30 13.34

60 26.08

120 49.02

240 80.09

360 100.0

Example 7

393g of cefaclor was mixed with 200g of hydroxypropylmethylcellulose, 20g of calcium carbonate, lOg of sodium bicarbonate and lOg of citric acid. The mixture was granulated using 160ml of 70% ethanol containing lOg of hydroxypropylmethylcellulose phthalate, and the granules were dried at 35 °C to a moisture, content of below 3%, and then, passed through No. 20 mesh. - 12 -

The granules thus obtained were mixed; with 20g of hydroxypropylmethylcellulose, 2g of sodium bicarbonate and 43g of microcrystalline cellulose. Added thereto were 3g of colloidal silicon dioxide and 6g of magnesium stearate which had previously been sieved through No. 40 mesh. The resulting mixture was formed into tablets by using a conventional press-tableting machine.

The dissolution rate of cefaclor was measured as in Example 1 and the results are shown in Table VII.

Table VII

Time ( hour ) Cumulative Dissolution rate(%)

0.5 2.2

1 5.3

2 10.5

5 23.7

12 50.3

18 75.1

24 100.0

Example 8

393g of cefaclor was mixed with 30g of hydroxypropyl- methylcellulose, 20g of calcium carbonate, lOg of sodium bicarbonate and lOg of citric acid. The mixture was granulated using 170ml of 95% ethanol containing lOg of ethylcellulose, and the granules were dried at 40 °C to a moisture content of below 3%, and then, passed through No. 20 mesh.

The granules thus obtained were mixed with 80g of hydroxypropylmethylcellulose, lOg of sodium bicarbonate, 20g - 13 - of calcium carbonate, 20g of microcrystalline cellulose, 3g of colloidal silicon dioxide and 3g of magnesium stearate. The resulting mixture was formed into tablets by using a conventional press-tableting machine.

When the tablet thus obtained was added to an artificial gastric fluid, it floated within 30 seconds to the upper layer and remained afloat for over 8 hours.

The dissolution rate of cefaclor was measured as in Example 1 and the results are shown in Table VIII.

Table VIII

Time(hour) Cumulative Dissolution rate(%)

0.5 7.94

1 14.80

2 26.60

4 46.34

6 68.99

8 91.69

10 97.65 12 100.0

Example 9

393g of cefaclor was mixed with 55g of hydroxypropylmethylcellulose, 20g of calcium carbonate, lOg of sodium bicarbonate and lOg of citric acid. The mixture was granulated using 190ml of 95% ethanol containing 30g of ethylcellulose, and the granules were dried at 40 °C to a moisture content of below 3%, and then, passed through No. 20 mesh.

The granules thus obtained were mixed with 35g of hydroxypropylmethylcellulose, lOg of sodium bicarbonate, 20g of calcium carbonate, 20g of microcrystalline cellulose, 3g of colloidal silicon dioxide and 3g of magnesium stearate. - 14 -

The resulting mixture was formed into tablets by using a conventional press-tableting machine.

When the tablet thus obtained was added to an artificial gastric fluid, it floated within 30 seconds to the upper layer and remained afloat for over 12 hours.

The dissolution rate of cefaclor was measured in the same manner in Example 1 and the results are shown in Table IX.

Table IX

Time ( hour ) Cumulative Dissolution rate(%)

0.5 8.17

1 14.20

2 23.43

4 39.27

6 51.14

8 65.43

10 76.37

12 86.54

14 94.65

16 100.0

Example 10

393g of cefaclor was mixed with 40g of hydroxypropylmethylcellulose, 20g of calcium carbonate, lOg of sodium bicarbonate and lOg of citric acid. The mixture was granulated using 170ml of 95% ethanol containing 30g of ethylcellulose, and the granules were dried at 40 °C to a moisture content of below 3%, and then, passed through No. 20 mesh.

The granules thus obtained were mixed with 50g of hydroxypropylmethylcellulose, lOg of sodium bicarbonate, 20g of calcium carbonate, 20g of microcrystalline cellulose, 3g - 15 - of colloidal silicon dioxide and 3g of magne.sium stearate, and the resulting mixture was formed into tablets by using a conventional press-tableting machine.

When the tablet thus obtained was added to an artificial gastric fluid, it floated within 30 seconds to the upper layer and remained afloat for over 20 hours.

The dissolution rate of cefaclor was measured as in Example 1 and the results are shown in Table X.

Table X

Time (hour ) Cumulative Dissolution rate(%)

1 9.27

2 16.37

3 29.10

4 38.87

8 47.22

10 54.17

12 60.47

16 73.62

20 83.30 24 97.10

Example 11

393g of cefaclor was mixed with llOg of hydroxypropylmethylcellulose, 20g of calcium carbonate, lOg of sodium bicarbonate and lOg of citric acid. The mixture was granulated using 210ml of 95% ethanol containing 20g of hydroxypropylmethylcellulose, and the granules were dried at 40°C to a moisture content of below 3%, and then, passed through No. 20 mesh.

The granules thus obtained were mixed with 30g of hydroxypropylmethylcellulose, lOg of sodium bicarbonate, 20g of calcium carbonate, 20g of microcrystalline cellulose, 3g 16 - of colloidal silicon dioxide and 3g of magnesium stearate. The resulting mixture was formed into tablets by using a conventional press-tableting machine.

The dissolution rate of cefaclor was measured as in Example 1 and the results are shown in Table XI.

Table XI

Time ( hour) Cumulative Dissolution rate(%)

1 5.79

2 10.10

4 17.41

6 30.18

8 42.43

10 55.63

12 67.54

16 76.43

20 86.27

24 100.0

Test Dissolution Test in vivo

The tablet prepared in accordance with Example 4 (cefaclor content: 375mg) was compared with a commercially available cefaclor capsule(Lilly Co., cefaclor content: 375mg) in an in vivo test using Beagle dogs. The dogs were fasted for 12 hours before administrating the drug together with 200ml of water. From each dog, 1.5ml blood samples were taken at 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours after the administration and each sample was centrifuged at 3,000 rpm, followed by methanol extraction. The cefaclor - 17 - concentration in blood was measured with high performance liquid chromatography, and the results are shown in Fig.l.

As shown in Fig. 1, the composition prepared in accordance with the present invention (♦) releases cefaclor in an improved manner for a longer period of time as compared with the commercially available cefaclor capsule (D), demonstrating the superiority of the composition of the present invention over conventional compositions in terms of sustained release characteristics. While the invention has been described with respect to the specific embodiments, it should be recognized that various modifications and changes may be made by those skilled in the art to the invention which also fall within the scope of the invention as defined by the appended claims.

Claims

- 18 -What is claimed is:

1. A sustained-release composition comprising 30 to 90 wt% of cefaclor, 5 to 60 wt% of a hydroswelling polymer and 1 to 10 wt% of a salt based on the total weight of the composition, said salt being capable of releasing gaseous C0₂ in a gastric environment.

2. The composition of claim 1, wherein the salt is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium sesquicarbonate, and a mixture thereof.

3. The composition of claim 1, wherein the salt is sodium bicarbonate.

4. The composition of claim 1, wherein the hydroswelling polymer is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcelluose, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium alginate and a mixture thereof.

5. The composition of claim 1 further comprising an organic acid selected from the group consisting of citric acid, tartaric acid, maleic acid and a mixture thereof.

6. The composition of claim 1 or 5 further comprising a foaming buffer selected from the group consisting of calcium carbonate, magnesium carbonate and a mixture thereof.

7. A pharmaceutical formulation comprising the composition of claim 1 and a pharmaceutically acceptable excipient and/or carrier.