KR100296413B1 - Sustained released tablet containing cefaclor - Google Patents

Abstract

PURPOSE: Provided are a sustained released tablet containing cefaclor and maintaining its blood level for long time despite administration once a day and its manufacturing method. CONSTITUTION: The sustained released tablet contains 30 to 90 wt.% of Cefaclor; 5 to 60 wt.% of hydroxypropyl methylcellulose or sodium carboxymethylcellulose; 1 to 10 wt.% of sodium hydrogen carbonate as a foam-forming agent; 1 to 2 wt.% of a foam-forming assistant selected from the group consisting of citric acid, tartaric acid and malic acid; and 2 to 7 wt.% of calcium carbonate or magnesium carbonate. The sustained released tablet may further contain a diluent selected from cellulose, pectin, sodium alginate, chitosan, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, gelatin, sucrose, lactose, mannitol, ethylcellulose and magnesium aluminum silicate.

Description

Sephacler-containing slow-release tablets

FIG. 1 shows the change in the concentration of Sephacler in blood when 375 mg of Sepaclecapcel (Daewoong Lili) and sustained-release tablet (Sepacler 375mg) according to the present invention are administered to beagle dogs.

□: Changes in blood concentration when Sephaclocapcel 375 mg (Daewoong Lilly) is administered

◆: Changes in blood concentrations when tablets (Sepacller 375mg) are administered according to the present invention.

The present invention relates to a sephacller-containing sustained-release tablet and a method for preparing the same, and more particularly, to 30-90 wt% of Sephacller, 5-60 wt% of swellable polymer, and 1-10 wt% of sodium hydrogencarbonate. It relates to a sephacller-containing sustained-release tablet and a method for producing the same.

Cefaclor is an oral cephalosporin-based antibiotic that has a high therapeutic effect on upper respiratory tract infections, lower respiratory tract infections, sinusitis adjuvant therapy, otitis media, urinary tract infections, and skin or skin tissue infections. It has a gastrointestinal tract absorption area and is stable when pH is less than 4.5 in aqueous solution, but it is easily inactivated when it is more than that. The half-life of blood in the body is used by three times a day within 1 hour.

Conventional techniques related to sustained-release preparations using the Sephacller as active ingredients are disclosed in U.S. Patent No. 4,713,247 (trade name: L-Kepral). (Siono, Japan) as a capsule containing rapid release pellets and sustained release pellets at 6: 4, the rapid release pellets dissolve in the stomach to release the drug, and the sustained release pellets dissolve in the intestine at a constant rate. The drug should be taken twice a day (2 capsules) to absorb the drug. In addition, U.S. Patent No. 4,968,508 (trade name: Cycler CD) , Lilly, USA), a matrix-type tablet using enteric and gastric polymers as a sustained release base, and should be taken twice daily as a drug designed to release the drug at a constant rate regardless of the pH of the gastrointestinal tract. do.

However, the sustained release formulations disclosed in U.S. Patent No. 4,713,247 and U.S. Patent No. 4,968,508 are all taken twice daily, and are sustained by once-a-day appilication. There is a problem that cannot be harmonized. That is, since the conventional sustained-release preparation is designed to release the drug (sepacller) only at a constant rate, a large amount of sefackler has to be used to sustain the sustained release in a daily dosage form. Too much concentration can cause side effects.

Thus, the present inventors conducted a study to develop a new Sephacller-containing sustained-release formulation that can maintain blood levels continuously even after administration only once a day, Separcler 30-90% by weight, based on the total weight of the tablet, Sustained-release formulations that can be administered once a day as well as twice-daily formulations when prepared and administered as a sephacller-containing sustained-release tablet containing 5 to 60% by weight of swellable polymer and 1 to 10% by weight of sodium hydrogencarbonate It has been found that the present invention can be completed to complete the present invention.

That is, the tablet according to the present invention generates bubbles by contact with gastric juice after oral administration, and the density of the preparation is smaller than the specific gravity of the gastric juice so that it is suspended in gastric juice and then swelling of the swellable polymer is gradually released into the tablet. It is designed to be a sustained release formulation, and by controlling the content of the swellable polymer and sodium bicarbonate, there is an advantage of controlling the release rate of the Sephacl.

Hereinafter, the present invention will be described in detail.

An object of the present invention is to provide a sephacller-containing sustained-release tablet containing 30 to 90% by weight of sephackler, 50 to 60% by weight of swellable polymer, and 1 to 10% by weight of sodium hydrogencarbonate.

It is also an object of the present invention to provide a method for producing the tablet.

Hereinafter, the present invention will be described in more detail.

Sephacller used as a drug in the tablet according to the present invention is preferably 30 to 90% by weight based on the total weight of the tablet, more preferably 60% or more in consideration of the size of the preparation.

The sodium hydrogen carbonate contained in the tablet according to the present invention is preferably used in an amount of 1 to 10% by weight and more preferably in an amount of 1 to 5% by weight based on the total weight of the tablet as the bubble generator. If the content of sodium bicarbonate is too high, the amount of bubbles is generated a lot, it may irritate the stomach, the tablet may disintegrate or lose the sustained release.

In addition, the tablet according to the present invention can prevent problems that may occur due to a temporary increase in the pH of the stomach due to food intake by including organic acids such as citric acid, tartaric acid, malic acid as a bubble generating aid. In addition, the tablet according to the present invention may include calcium carbonate or magnesium carbonate as a bubble generating buffer to prevent the disintegration caused by excessive foaming.

The swellable polymers contained in the tablets according to the present invention are preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidone, sodium alginate, and the like, of which hydroxypropyl methyl cellulose or carboxymethyl Sodium cellulose is most preferred. The content of the swellable polymer contained in the tablet according to the present invention is preferably 5 to 60% by weight based on the total weight of the tablet, and by controlling the content of the swellable polymer, it is possible to effectively change the release rate of the Sephacl. In other words, the higher the content of the swellable polymer, the slower the release rate of the sepacller, the lower the content, the faster the release rate of the sepacller.

Tablets according to the invention may be formulated containing excipients known and available in the pharmaceutical art. Excipients that may be included in the tablets according to the invention include microcrystalline cellulose, pectin, sodium alginate, chitosan, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate, Natural or fully synthetic or partially synthesized hydrophilic rubbers such as gelatin, sucrose, lactose, mannitol, ethylcellulose, magnesium aluminum silicate and the like.

The present invention includes a method for producing a sustained release tablet containing the above components. The method for preparing a sustained release tablet according to the present invention may be prepared by mixing the above components according to a conventional wet granulation method, preparing granules by mixing them with a known lubricant, but minimizing initial flotation time. In order to release the Sephacle slowly in the state, the granules are prepared by mixing the Sepacle and the excipient with some swellable polymer and sodium hydrogen carbonate, and then mixing the remaining swellable polymer and sodium hydrogen carbonate together with the lubricant and the granule again. It is preferable to prepare accordingly. The glidants may be used glidants known and used in the pharmaceutical field, such as stearic acid, magnesium stearate, aerosol ^TM and the like. In addition, the bubble generator (sodium bicarbonate) contained in the granules is preferably 10 to 90% by weight, more preferably 50% or more of the total content.

In the above production method, when preparing a sustained-release tablet including a bubble generating aid and a bubble generating buffer, it is preferable to mix the bubble generating auxiliary such as citric acid, tartaric acid, malic acid when preparing granules, calcium carbonate or magnesium carbonate It is preferable to mix the bubble-forming buffer of dividing into granules and tableting.

Tablets according to the present invention prepared as described above can be arbitrarily adjusted the release rate of the sepacller as can be seen in the following examples, it can be designed to be administered not only twice a day tablets but also once a day. have.

Example 1

Sepacle 400g, 20g of hydroxypropylmethylcellulose, 20g of calcium carbonate, 10g of sodium bicarbonate, 10g of citric acid, 10g of hydroxypropylmethylcellulose phthalate, and 2g of aerosol were granulated with 140 ml of 70% ethanol solution, and then 40 The dried granules were dried by drying until the moisture content was 3% or less at 占 폚, and then sieved (No. 14 mesh). The granulated granules were mixed with 60 g of hydroxypropyl methyl cellulose, 20 g of calcium carbonate, 5 g of sodium bicarbonate, and 30 g of sodium carboxymethyl cellulose, followed by mixing 1 g of aerosol passed through a No. 40 mesh sieve and 3 g of magnesium stearate. After tableting with a compressed tablet press to prepare a tablet.

When the above-prepared tablets were placed in artificial gastric juice, they were immediately suspended within about 10 seconds after the administration, and floated in the upper layer of the liquid for 6 hours or more.

In addition, when the tablet prepared above was tested according to the Korean Pharmacopoeia Elution Test No. 2 using 900 ml of 0.1 N hydrochloric acid solution at 37 ° C., the results are shown in Table 1 below.

TABLE 1

Example 2

Sepacle 393g, 20g of hydroxypropylmethylcellulose, 20g of calcium carbonate, 10g of sodium bicarbonate, 10g of citric acid, 10g of hydroxypropylmethylcellulose phthalate, 140 ml of 70% ethanol solution was granulated, and the water content at 40 ° C. It was dried until it became 3% or less to prepare dry granules, and then sieved (16 mesh). The granulated dry granules were mixed with 80 g of hydroxypropyl methyl cellulose, 20 g of calcium carbonate, 5 g of sodium bicarbonate, and 25 g of microcrystalline cellulose. Then, 6 g of magnesium stearate passed through No. 30 mesh was mixed again, followed by compression tableting. Tablets were prepared.

When the above-prepared tablets were placed in artificial gastric juice, they were suspended immediately after administration and floated at the upper layer of the liquid for at least 6 hours.

When the dissolution test was carried out in the same manner as in Example 1 with the tablet prepared above, the results are shown in Table 2 below.

TABLE 2

Example 3

Sepacle 393g, 20g of hydroxypropylmethylcellulose, 20g of calcium carbonate, 10g of sodium bicarbonate, 10g of citric acid were mixed, and then, 10g of hydroxypropylmethylcellulose phthalate was dissolved in 120 ml of 95% ethanol solution, and then granulated. The dried granules were dried at 40 ° C. until the water content was 3% or less, and then granulated (16 mesh). The granulated granules were mixed with 70 g of hydroxypropylmethyl cellulose, 15 g of calcium carbonate, 15 g of sodium bicarbonate, and 31 g of microcrystalline cellulose, and then again mixed with 3 g of aerosol and 3 g of magnesium stearate passed through a No. 40 mesh. Tablets were prepared by compression using a compression tablet.

When the above-prepared tablets were placed in artificial gastric juice, they were floated within about 30 seconds after administration and floated at the upper layer of the liquid for at least 6 hours.

When the dissolution test was carried out in the same manner as in Example 1 with the tablet prepared above, the results are shown in Table 3 below.

TABLE 3

Example 4

Sepacle 400g, 20g of hydroxypropylmethylcellulose, 20g of calcium carbonate, 10g of sodium bicarbonate, 10g of citric acid and 1g of aerosol were mixed, and then 10g of hydroxypropylmethylcellulose phthalate was dissolved in 120 ml of 95% ethanol solution. After granulation, the dried granules were dried at 40 ° C. until the water content was 3% or less, and then granulated (No. 16 mesh). The granulated granules were mixed with 70 g of hydroxypropyl methyl cellulose, 20 g of calcium carbonate, 5 g of sodium bicarbonate, and 40 g of microcrystalline cellulose, and then again mixed with 2 g of aerosol and 3 g of magnesium stearate passed through a No. 30 mesh sieve. Tablets were prepared by compression using a compression tablet press.

When the above-prepared tablets were placed in artificial gastric juice, they were suspended within about 30 seconds after administration and floated at the upper layer of the liquid for at least 5 hours.

When the dissolution test was carried out in the same manner as in Example 1 with the tablet prepared above, the results are shown in Table 4 below.

TABLE 4

Example 5

Sepacle 393g, hydroxypropylmethylcellulose 110g, calcium carbonate 20g, sodium hydrogencarbonate 5g, citric acid 10g was mixed, granulated with a solution of 10g hydroxypropylmethylcellulose phthalate dissolved in 160g 70% ethanol solution, 35 The dried granules were dried until the water content was 3% or less at 0 ° C., and then granulated (16 mesh). The dry granulated granules were mixed with 10 g of hydroxypropyl methyl cellulose, 2 g of sodium bicarbonate, and 43 g of microcrystalline cellulose, and then again mixed with 3 g of aerosol and 6 g of magnesium stearate passed through a No. 40 mesh sieve, followed by compression tableting. Tablets were prepared.

When the above-prepared tablets were placed in artificial gastric juice, they were floated within about 30 seconds after administration and floated at the upper layer of the liquid for at least 10 hours.

When the dissolution test was carried out in the same manner as in Example 1 with the tablet prepared above, the results are shown in Table 5 below.

TABLE 5

Example 6

Sepacle 393g, 20g of hydroxypropylmethylcellulose, 20g of calcium carbonate, 10g of sodium bicarbonate, 10g of citric acid were mixed, and then 10g of hydroxypropylmethylcellulose phthalate was dissolved in 140 ml of 95% ethanol solution. The dried granules were dried at 40 ° C. until the water content was 3% or less, and then granulated (16 mesh). The granulated granules were mixed with 60 g of hydroxypropyl methyl cellulose, 10 g of sodium bicarbonate, 20 g of calcium carbonate, and 31 g of microcrystalline cellulose. Then, 3 g of aerosil and 3 g of magnesium stearate passed through No. 30 mesh were mixed again and then compressed. Tablets were prepared by tableting with a tablet press.

When the above-prepared tablets were placed in artificial gastric juice, they were floated within about 30 seconds after administration and floated at the upper layer of the liquid for at least 6 hours.

When the dissolution test was carried out in the same manner as in Example 1 with the tablet prepared above, the results are shown in Table 6 below.

TABLE 6

Example 7

Sepacle 393g, 200g of hydroxypropylmethylcellulose, 20g of calcium carbonate, 10g of sodium bicarbonate, 10g of citric acid were mixed, and then granulated with a solution of 10g of hydroxypropylmethylcellulose phthalate dissolved in 160g of 70% ethanol solution, and then 35 The dried granules were prepared by drying until the moisture content was 3% or less at 0 ° C., followed by sizing (16 mesh). The dry granulated granules were mixed with 20 g of hydroxypropylmethyl cellulose, 2 g of sodium bicarbonate, and 43 g of microcrystalline cellulose, and then again mixed with 3 g of aerosol and 6 g of magnesium stearate passed through a No. 40 mesh sieve, and then pressed with a compression tablet. Tablets were prepared.

When the above-prepared tablets were placed in artificial gastric juice, they were floated within about 30 seconds after administration and floated at the upper layer of the liquid for at least 10 hours.

When the dissolution test was carried out in the same manner as in Example 1 with the tablet prepared above, the results are shown in Table 7 below.

TABLE 7

[Test Example 1]

Beagle dogs fasted for 12 hours were taken the tablets (Sepacller 375mg) and Sephaclercapcel 375mg (Daewoongli) prepared in Example 4 with 200ml of purified water, and then, 30 minutes, 1 hour, 2 hours after administration. Every 1.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours, 1.5 ml of blood was collected, centrifuged at 3000 rpm, extracted with methanol, and the Sepacle concentration was analyzed by high-performance liquid chromatography. , And the result is shown in FIG.

As can be seen in FIG. 1, the elution pattern of Sephacller from the tablet designed according to the present invention shows a pattern of a typical sustained release tablet.

Claims (1)

Sephacler 30-90 weight percent, based on the total weight of the tablet; Hydroxypropyl methylcellulose or carboxymethylcellulose sodium 5-60 wt%: sodium hydrogencarbonate 1-10 wt%; 1-2% by weight of the foaming aid selected from the group consisting of citric acid, tartaric acid, and malic acid; And 2-7% by weight of calcium carbonate or magnesium carbonate.