WO2005115347A1

WO2005115347A1 - Dispersible tablet comprising beta lactam antibiotics and process for preparing the same

Info

Publication number: WO2005115347A1
Application number: PCT/KR2004/003228
Authority: WO
Inventors: Jong-Bum Park; Ok-Ja Jeong; Choong-Ho Yoo
Original assignee: Sam-A Pharmaceuticals Co., Ltd.
Priority date: 2004-05-31
Filing date: 2004-12-09
Publication date: 2005-12-08
Also published as: KR100515311B1; JP2006527064A; CN1767818A; KR20050002738A

Abstract

The present invention relates to a dispersible tablet formulation comprising beta lactam antibiotics in which a beta lactam antibiotic is formulated with a salt of clavulanic acid in a tablet form to be easily administered upon the disintegration in water, and a process for preparing the same. The process for preparing the dispersible tablet formulation comprises the steps of: mixing a beta lactam antibiotic and a salt of clavulanic acid with a disintegrant, a lubricant and a binder and then applying the mixture to a roller compactor to obtain drytype granules; and, mixing the dry-type granules with an excipient, a disintegrant, a lubricant and a binder, and compressing the mixture to give a tablet. The dispersible tablet formulation can be practically applied for the treatment of diseases requiring beta lactam antibiotics, since it can be easily taken by the infants or older patients being troubled with oral administration with improved disintegration rate and dispersion property.

Description

DISPERSIBLE TABLET COMPRISING BETA LACTAM ANTIBIOTICS AND PROCESS FOR PREPARING THE SAME

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a dispersible tablet formulation comprising beta lactam antibiotics and a process for preparing the same, more specifically, to a dispersible tablet formulation comprising beta lactam antibiotics, in which a beta lactam antibiotic is formulated with a salt of clavulanic acid in a tablet form to be easily administered upon disintegration in water, and a process for preparing the same.

Background of the Invention Amoxicillin, one of the beta lactam antibiotics, is also called a semi-synthetic penicillin or spectrum penicillin and used most widely as an antibacterial agent effective for the treatment of sore throat or tonsillitis. As amoxicillin has been used frequently, amoxicillin- resistant bacterial strains with beta lactamase activity become prevalent. Therefore, amoxicillin is formulated in a mixed form with a salt of clavulanic acid which inhibits beta lactamase activity. The most frequently used formulation where amoxicillin and potassium clavulanate are mixed at a ratio of 2:l(w/w), co-amoxiclav formulation is commercially available under the trademark of Augmentin™ and produced in a dosage form of film-coated tablet, dry- syrup, etc. The salt of clavulanic acid comprised in the said formulation is very sensitive to moisture and readily decomposed by small amount of water, so various studies to solve this problem have been made in the art. For example, U.S. Patent 6,051,255 discloses a tablet formulation which does not allow outer moisture to contact with the salt of clavulanic acid by film-coating a compressed mixture of amoxicillin and a salt of clavulanic acid. The film-coated tablet has revealed no particular problem for the adults but made troubles upon oral administration for the infants or older patients who dislike swallowing because of feeling of alien substances. As the alternatives for overcoming the problems of the film-coated tablet, various types of formulation in which amoxicillin and a salt of clavulanic acid are not formulated in a tablet form have been prepared and administered to the infants or older patients. For example, WO 01/45667 discloses water-soluble powders or granules comprising amoxicillin trihydrate and a salt of clavulanic acid. However, the water-soluble powders or granules are formulated to absorb water easily, which makes the unpacked formulation contact with water directly or indirectly, finally to decompose a salt of clavulanic acid and gradually decrease the efficacy of unused medicine as time goes by. To overcome the said problem, methods of slowing down the decomposition by refrigerating the unpacked formulation has been attempted, which ended in failure to provide the ultimate solution. Moreover, the methods lead the unpacked formulation under cold-storage to be partly frozen or recrystallized by absorbed water, so the valid amount cannot be prescribed for the patients. Further, WO 00/03695 discloses a liquid aqueous pharmaceutical suspension formulation containing amoxicillin trihydrate, a salt of clavulanic acid and cellulose as a filler. Dry-syrup is prepared by adding a sweetener to a suspension formulation, which is currently sold in large quantities as antibiotics formulation comprising amoxicillin and a salt of clavulanic acid. But, the suspension formulation including the dry-syrup is too hygroscopic to be resistant to moisture, which raises problems of easy decomposition of a salt of clavulanic acid or efficacy change owing to long storage. As another alternative for overcoming the drawbacks of the afore-mentioned water-soluble powders, granules and suspensions, a dispersible tablet in which amoxicillin and a salt of clavulanic acid are formulated has been administered to the infants or older patients. For example, WO 04/06917 discloses a dispersible tablet formulation prepared by mixing and compressing amoxicillin and croscarmellose sodium as a disintegrant to give granules, adding to the granules a mixture of potassium clavulanate, croscarmellose sodium as a disintegrant, silicon dioxide as a desiccant, microcrystalline as an excipient, magnesium stearate as a lubricant, flavor, sweetener and food colors and compressing the mixture. The dispersible tablet formulation, however, has caused some inconveniences in the course of administration, e.g., it takes more than 2 minutes to be disintegrated in water even if it contains no binder to improve dispersibility and some patients may feel alien substance due to the relatively large size of disintegrated particle. To solve the said problems, various studies have been made in the art, however, successful accomplishments have not been reported until now. Under the circumstance, there are strong reasons for developing a dispersible tablet formulation comprising amoxicillin and a salt of clavulanic acid, which allows simple and easy administration of the tablet with improved disintegration rate and dispersion property.

SUMMARY OF THE INVENTION

The present inventors have made an effort to develop a dispersible tablet formulation comprising amoxicillin and a salt of clavulanic acid whose administration can be made in a simple and easy manner, and found that the desired dispersible tablet formulation can be prepared by: mixing a beta lactam antibiotic and a salt of clavulanic acid with a disintegrant, a lubricant and a binder and then applying the mixture to a roller compactor to obtain dry-type granules; and, mixing the dry-type granules with an excipient, a disintegrant, a lubricant and a binder, and compressing the mixture to give a tablet. They also verified that the dispersible tablet formulation can be practically applied for the treatment of diseases requiring beta lactam antibiotics, since it can be easily taken by the infants or older patients being troubled with oral administration.

A primary object of the present invention is, therefore, to provide a process for preparing a dispersible tablet formulation comprising beta lactam antibiotics with improved disintegration rate and dispersion property.

The other object of the invention is to provide a dispersible tablet formulation comprising beta lactam antibiotics prepared by the said process.

DETAILED DESCRIPTION OF THE INVENTION

The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics comprises the steps of: (i) mixing a beta lactam antibiotic and a salt of clavulanic acid with a disintegrant, a lubricant and a binder, and then applying the mixture to a roller compactor to obtain dry-type granules; and, (ii) mixing the dry-type granules with an excipient, a disintegrant, a lubricant and a binder, and, compressing the mixture to give a tablet. In practicing the present invention, the beta lactam antibiotic is, not limited thereto, preferably penicillin antibiotic, more preferably, penicillin, amoxicillin, ampicillin, ciclacillin, epicillin, phenethicillin or pivampicillin, and the salt of clavulanic acid is, not limited thereto, preferably potassium clavulanate. As reported previously in the art, a beta lactam antibiotic and a salt of clavulanic acid is preferably mixed at a ratio of 2:1 to 14:l(w/w), most preferably 4:l(w/w), and the mixture of a beta lactam antibiotic and a salt of clavulanic acid is preferably included in the dispersible tablet formulation at a ratio of 15 to 40%(w/w). Further, the disintegrant of the step(i) is, not limited thereto, preferably crospovidone, croscarmellose sodium, sodium starch glycolate, potassium carboxymethyl cellulose, pregelatinized starch or a mixture thereof, and the disintegrant is, not limited thereto, preferably included in the dispersible tablet formulation at a ratio of 3 to 10% (w/w) . Next, the lubricant of the step(i) is, not limited thereto, preferably magnesium stearate, silicon dioxide, talc, polyethylene glycol, stearic acid or a mixture thereof, and the lubricant is, not limited thereto, preferably included in the dispersible tablet formulation at a ratio of 0.1 to 5% (w/w) . The binder of the step(i) is, not limited thereto, preferably copovidone, povidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose or a mixture thereof, and the binder is, not limited thereto, preferably included in the dispersible tablet formulation at a ratio of 0.1 to 7.5% (w/w) . Still further, in the step(i), a desiccant or a foaming agent may be further added to the mixture of a beta lactam antibiotic and a salt of clavulanic acid along with a disintegrant, a lubricant and a binder, where the desiccant is, not limited thereto, preferably silicon dioxide, synthetic aluminium silicate, light anhydrous silicic acid or a mixture thereof, and the desiccant is, not limited thereto, preferably included in the dispersible tablet formulation at a ratio of 0.1 to 10% (w/w) as the conventional use. The foaming agent is, not limited thereto, preferably citric acid, tartaric acid, alginic acid, malic acid, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate or a mixture thereof, and the foaming agent is, not limited thereto, preferably included in the dispersible tablet formulation at a ratio of 1 to 5% (w/w) . Meanwhile, the excipient of the step(ii) is, not limited thereto, preferably microcrystalline cellulose, low substituted hydroxypropyl cellulose, lactose, calcium hydrogen phosphate, corn starch, mannitol, sorbitol, xylitol or a mixture of thereof, and the excipient is, not limited thereto, preferably included in the dispersible tablet formulation at a ratio of 30 to 75% (w/w). The disintegrant of the step(ii) is, not limited thereto, preferably crospovidone, croscarmellose sodium, sodium starch glycolate, potassium carboxymethyl cellulose, pregelatinized starch or a mixture thereof, and the disintegrant used in the step(ii) is, not limited thereto, preferably included in the dispersible tablet formulation at a ratio of 3 to 10% (w/w) . The lubricant of the step(ii) is, not limited thereto, preferably magnesium stearate, silicon dioxide, talc, polyethylene glycol, stearic acid or a mixture thereof and the lubricant used in the step(ii) is, not limited thereto, preferably included in the dispersible tablet formulation at a ratio of 0.1 to 5% (w/w) . The binder of the step(ii) is, not limited thereto, preferably copovidone, povidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose or a mixture thereof, and the binder used in step(ii) is, not limited thereto, preferably included in the dispersible tablet formulation at a ratio of 0.1 to 7.5% (w/w). Further, in practicing the step(ii), the excipient, disintegrant, lubricant and binder are mixed with the dry- type granules obtained in step(i) in one of the followings: powder form; dry-type granules obtained by mixing and compressing those materials; and, wet-type granules obtained by mixing those materials with water. Finally, in the step(ii), a foaming agent may be further added to the dry-type granules obtained in step(i) along with an excipient, a disintegrant, a lubricant and a binder. In this step, the foaming agent is, not limited thereto, preferably citric acid, tartaric acid, alginic acid, malic acid, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate or a mixture thereof, and the foaming agent used in step(ii) is, not limited thereto, preferably included in the dispersible tablet formulation at a ratio of 1 to 5% (w/w) .

The present inventors have made various efforts to develop a complex formulation of amoxicillin and a salt of clavulanic acid to be easily taken by the infants or older patients being troubled with oral administration, and paid attention to a dispersible tablet formulation disclosed in WO 04/06917, in which wet-type granules comprising amoxicillin is mixed with a salt of clavulanic acid and compressed to give a dispersed tablet for oral administration upon dispersion in water. And, the present inventors tried to improve the dispersible tablet formulation in terms of disintegration rate and dispersion property by way of: changing its ingredients and the composition ratios of the said ingredients; employing dry-type granules comprising amoxicillin and a salt of clavulanic acid, a disintegrant, a lubricant and a binder; and, optimizing the composition ratios of the disintegrant, lubricant and binder, and a foaming agent as an optional ingredient. In general, a lubricant and a binder should be used to prepare dry-type granules, where the binder promotes binding of each components. Naturally, the present inventors expected that the dispersible tablet formulation with dry-type granules comprising a mixture of amoxicillin and a salt of clavulanic acid showed lower disintegration rate than that disclosed in WO 04/06917, however the present formulation, contrary to the expectation, showed a high disintegration rate and excellent dispersion property. The present inventors prepared various dispersible tablet formulations with dry-type granules comprising amoxicillin and a salt of clavulanic acid and the optimized composition ratios of disintegrant, lubricant, binder and excipient, and measured the disintegration time and dispersion property of each of the formulations. As a result, it was verified that all of the various dispersible tablet formulations with dry-type granules showed more improved disintegration rate and dispersion property than that disclosed in WO 04/06917, and especially, a dispersible tablet formulation comprising a foaming agent was disintegrated faster than foaming agent-free formulation. Accordingly, it could be concluded that the dispersible tablet formulation of present invention assures more efficacious therapy than prior art formulation by employing dry-type granules to be administered simply and absorbed easily into the body. Meanwhile, the present inventors found that a lubricant should be included in both steps of obtaining dry-type granules and compressing the mixture comprising the dry-type granules to give a dispersible tablet formulation, that is, during the process of applying a mixture of a beta lactam antibiotic, a salt of clavulanic acid, a disintegrant, a lubricant and a binder to a roller compactor to obtain dry-type granules, the lubricant prohibits the mixture from sticking to the roller compactor which obstructs the continuous process of obtaining dry- type granules. Besides, during the subsequent process of compressing the mixture of dry-type granules, excipient, disintegrant, lubricant and binder to give a tablet, the use of lubricant also prohibits the mixture from sticking to the punch of the compressor which obstructs the continuous compressing process. Accordingly, it was verified that a lubricant should be included in both steps of obtaining dry-type granules and compressing a mixture to prepare a dispersible tablet formulation. As mentioned above, the dispersible tablet formulation of present invention is inherently prepared to comprise amoxicillin. However, the invented formulation, considering that it is designed to use a salt of clavulanic acid inhibiting beta lactamase of amoxicillin-resistant bacteria, can be applied to comprise various pharmaceuticals which may be used as a complex formulation with a salt of clavulanic acid. For example, if the complex formulations mixed with a salt of clavulanic acid and beta lactam antibiotics such as ampicillin, penicillin, ciclacillin, epicillin, phenethicillin, pivampicillin are prepared in a form of the dispersible tablet of present invention, the dispersible tablet formulations could overcome the tolerance to beta lactam antibiotics with improved disintegration rate and dispersion property assuring simple and easy administration and absorption. To verify this expectation, penicillin and pivampicillin were mixed with potassium clavulanate, respectively, and each of dispersible tablet formulations prepared by the above way was disintegrated in water and disintegration time was measured. As a result, all of the dispersible tablet formulations were completely disintegrated in a short period of 30 to 40 sec, demonstrating that the invented dispersible tablet formulations can be applied to various beta lactam antibiotics and amoxicillin as well.

The dispersible tablet formulation comprising beta lactam antibiotics thus prepared comprises an active ingredient of a mixture of a beta lactam antibiotic and a salt of clavulanic acid 15 to 40% (w/w), and a disintegrant 6 to 20% (w/w), a lubricant 0.1 to 10% (w/w) , a binder 0.1 to 15% (w/w) , an excipient 30 to 75% (w/w) of the dispersible tablet formulation, and optionally a foaming agent, a desiccant or a mixture thereof, preferably at the composition ratios of 0.1 to 10% (w/w) for dessicant and 2 to 10% (w/w) for foaming agent. The dispersible tablet formulation can be practically applied for the treatment of diseases requiring beta lactam antibiotics, since it can be easily taken by the infants or older patients being troubled with oral administration with improved disintegration rate and dispersion property.

The present invention is further illustrated in the following examples, which should not be taken to limit the scope of the invention.

Example 1: Preparation of Dispersible Tablet Formulations Comprising Amoxicillin and Evaluation of Disintegration Property First, a dispersible tablet formulation was prepared by employing wet-type granules as disclosed in PCT international publication WO 04/06917: 231. Omg of amoxicillin, 12.5mg of croscarmellose sodium, 0.5mg of dye and some water were mixed to obtain wet-type granules. Then, to the wet-type granules thus obtained were added 104. mg of potassium clavulanate, 12.5mg of croscarmellose sodium, 20mg of flavour, 0.5mg of dye, 5mg of silicon dioxide, lOmg of aspartame, 200mg of microcrystalline cellulose and 7.5mg of magnesium stearate, mixed and compressed to prepare 600mg of a dispersible tablet formulation. And then, another dispersible tablet formulation was prepared similarly as the above with an exception of employing dry-type granules instead of wet-type granules, where the dry-type granules were prepared by means of a binder: that is, 231. Omg of amoxicillin, 104.4mg of potassium clavulanate, 12.5mg of croscarmellose sodium, 3.5mg of magnesium stearate, 0.5mg of dye and 3mg of copovidone were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and a screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 12.5mg of croscarmellose sodium, 14mg of flavour, 0.5mg of dye, 3mg of copovidone, 5mg of silicon dioxide, lOmg of aspartame, 200mg of microcrystalline cellulose and . Omg of magnesium stearate, mixed and compressed to prepare 600mg of a dispersible tablet formulation. Each of the dispersible tablet formulations prepared by the said two methods were disintegrated in 5mL of distilled water and the time required to reach below 200 mesh in the size of particles was measured 10 times by the naked eye, and the average disintegration time was measured, and then the distribution of sizes of disintegrated particles was determined by the aid of Automatic Particle Size Analyzer (see: Table 1).

Table 1: Disintegration Property of Dispersible Tablet Formulations Prepared by Employing Dry-type Granules and Wet-type Granules as Intermediates

As shown in Table 1 above, it was clearly demonstrated that a dispersible tablet formulation prepared by employing dry-type granules was disintegrated faster than that prepared by employing wet-type granules. These results were contradictory to our expectation that: the dispersible tablet formulation prepared by employing dry- type granules will be disintegrated faster than that prepared by employing wet-type granules, since a binder such as copovidone is generally used to bind each components to give hard disintegration property. Further, it was also examined that the dispersible tablet formulation prepared by employing dry-type granules, was disintegrated in water in a particle size much finer than that prepared by employing wet-type granules. Accordingly, it was concluded that the said results were caused by two factors of different intermediates (i.e. , dry-type granules and wet-type granules) and different process for preparing the formulations, considering that: each of the formulations prepared by employing the said two different intermediates with the same ingredients and amounts thereof except for adding a binder in the dry-type granules by the decreased amount of some flavor which has no effect on the disintegration rate. Since the disintegrant and the binder may, exert a crucial influence on the disintegration property such as disintegration rate and the dispersibility in the course of preparing a dispersible tablet formulation with dry-type granules, the ratios of disintegrant and binder showing the most excellent disintegration property were determined, and whether the ratios of lubricant and excipient have effect on the disintegration property were also verified in the following experiments.

Example 2 : Optimization of Composition Ratios of Ingredients Contained in Dispersible Tablet Formulation

In a dispersible tablet formulation with an intermediate of dry-type granules prepared in Example 1, each of the ratios of a disintegrant, a binder, a lubricant and an excipient to give the most excellent disintegration rate and dispersion property was determined, respectively.

Example 2-1: Determination of Optimized Composition Ratio of Disintegrant 120mg of amoxicillin, 30mg of potassium clavulanate, 5mg of magnesium stearate, croscarmellose sodium and 2mg of copovidone were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added croscarmellose sodium, 5mg of silicon dioxide, 3mg of copovidone, microcrystalline cellulose and 5mg of magnesium stearate, mixed and compressed to prepare 500mg of a dispersible tablet formulation, and the disintegration time of each formulations was measured by the same method as in Example 1 (see: Table 2a). In the course of preparing the dry-type granules and formulations, the amounts of croscarmellose sodium(ccs) as a disintegrant and microcrystalline cellulose (mcc) as an excipient were varied as followings, to prepare dispersible tablet formulations containing a disintegrant at a ratio of 0, 5, 10, 15, 20, 25 or 30% (w/w) , respectively: Omg ccs, 330mg mcc; 25mg ccs, 305mg mcc; 5Omg ccs, 28Omg mcc; 75mg ccs, 255mg mcc; lOOmg ccs, 230mg mcc; 125mg ccs, 205mg mcc; and, 150mg ccs, 180mg mcc.

Table 2a: Effects of Composition Ratio of Disintegrant on Disintegration Time

As shown in Table 2a above, the disintegration time decreased abruptly in the range of above 10% (w/w) disintegrant, and in the range of above 20% (w/w) , it did not decrease any more. To determine the composition ratio of disintegrant more specifically, each of dispersible tablet formulations containing a disintegrant at a ratio of 5, 6, 7, 8, 9, 10, 15, 16, 17, 18, 19 or 20% (w/w) was prepared, and the disintegration time was measured, respectively (see: Table 2b).

Table 2b: Effects of Composition Ratio of Disintegrant on Disintegration Time

As shown in Table 2b above, the disintegration time decreased abruptly in the range of above 6% (w/w) disintegrant, and in the range of above 20% (w/w) , it did not decrease any more.

Example 2-2: Determination of Optimized Composition Ratio of Binder

120mg of amoxicillin, 30mg of potassium clavulanate, 5mg of magnesium stearate, 20mg of croscarmellose sodium and copovidone were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 20mg of croscarmellose sodium, 5mg of silicon dioxide, copovidone, microcrystalline cellulose and 5mg of magnesium stearate, mixed and compressed to prepare 500mg of a dispersible tablet formulation, and the disintegration time of each formulations was measured by the same method as in Example 1 (see: Table 3a). In the course of preparing the dry-type granules and formulations, the amounts of copovidone ("co- pvp") as a binder and microcrystalline cellulose ("mcc") as an excipient were varied as followings, to prepare dispersible tablet formulations containing a disintegrant at a ratio of 0, 3, 6, 9, 12, 15 or 18% (w/w) , respectively: Omg co-pvp, 295mg mcc; 15mg co-pvp, 280mg mcc; 30mg co-pvp, 265mg mcc; 45mg co-pvp, 250mg mcc; 60mg co-pvp, 235mg mcc; 75mg co-pvp, 22Omg mcc; and, 9Omg co-pvp, 205mg mcc.

Table 3a: Effects of Composition Ratio of Binder on Disintegration Time

As shown in Table 3a above, with no addition of binder, dry-type granules were not prepared properly and the disintegration time could not be measured, and with the addition of above 15% (w/w) binder, the disintegration time increased abruptly. To determine composition ratio of binder more specifically, each of dispersible tablet formulations containing a binder at a ratio of 15, 16, 17 or 18% (w/w) was prepared, and the disintegration time was measured, respectively (see : Table 3b).

Table 3b: Effects of Composition Ratio of Binder on Disintegration Time

Composition Disintegration Time

As shown in Table 3b above, the disintegration time increased abruptly in the range of above 16% (w/w) binder, indicating that below 15% (w/w) of binder is preferred.

Example 2-3: Determination of Optimized Composition Ratio of Lubricant

120mg of amoxicillin, 30mg of potassium clavulanate, 50mg of croscarmellose sodium, 4Omg of copovidone and magnesium stearate were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 50mg of croscarmellose sodium, 5mg of silicon dioxide, 35mg of copovidone, microcrystalline cellulose and magnesium stearate, mixed and compressed to prepare 500mg of a dispersible tablet formulation, and the disintegration time of each formulations was measured by the same method as in Example 1 (see: Table 4). In the course of preparing the dry-type granules and formulations, the amounts of magnesium stearate ("MgSA") as a lubricant and microcrystalline cellulose ("mcc") as an excipient were varied as followings, to prepare dispersible tablet formulations containing a lubricant at a ratio of 0, 1, 5, 10, 15, 20 or 30% (w/w) , respectively: Omg MgSA, 170mg mcc; 5mg MgSA, 165mg mcc; 25mg MgSA, 145mg mcc; 50mg MgSA, 120mg mcc; 75mg MgSA, 95mg mcc; lOOmg MgSA, 70mg mcc; and, 150mg MgSA, 20mg mcc.

Table 4 : Effects of Composition Ratio of Lubricant on Disintegration Time

As shown in Table 4 above, with no addition of lubricant, dry-type granules were not prepared properly, and the disintegration time could not be measured, and with the addition of at least 1% (w/w) lubricant, the amount of lubricant had no effect on the disintegration time.

Example 2-4: Determination of Optimized Composition Ratio of Excipient

Each of the dispersible tablet formulations containing various composition ratios of a disintegrant, a binder and a lubricant determined in Examples 2-1 to 2-3 was prepared, respectively. 60mg of amoxicillin, 15mg of potassium clavulanate, magnesium stearate ("MgSA-1") , croscarmellose sodium("ccs- 1") and copovidone ("co-pvp-1") were mixed and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, 500mg of a dispersible tablet formulations containing excipient at a ratio of 0, 10, 20, 30, 40, 50, 60, 70 or 75% (w/w) were prepared by mixing and compressing the said dry-type granules with 5mg of silicon dioxide, magnesium stearate ("MgSA-2") , croscarmellose sodium("ccs-2") , copovidone ("co-pvp-2") and microcrystalline cellulose ("mcc") , whose amounts were shown in Table 5a below. Table 5a: Amounts of Each Ingredients Contained in a Dispersible Tablet Formulation (unit : mg)

The disintegration time of each dispersible tablet formulations was measured by the same method as in Example 1, respectively (see : Table 5b).

Table 5b: Effects of Composition Ratio of Excipient on Disintegration Time

As shown in Table 5b above, with the addition of over 30% excipient, a dispersible tablet could be prepared properly, and with the addition of excipient allowing the proper preparation of a dispersible tablet formulation, the amount had no relation with the disintegration time. However, the composition ratio of excipient was optimized to be about 75% (w/w) , in view of the composition ratios determined in Examples 2-1 to 2-3. Summarizing the results of Examples 2-1 to 2-4, the optimum ratio showing the most excellent disintegration rate and dispersion property in a dispersible tablet formulation with dry-type granules as intermediate was: 6 to 20% (w/w) disintegrant, 0.1 to 15% (w/w) binder, 30 to 75% (w/w) excipient, and not specifically limited content of lubricant.

Example 3: Preparation of Dispersible Tablet Formulations with Varied Composition Ratios Dispersible tablet formulations with dry-type granules comprising an amoxicillin and a salt of clavulanic acid and varied composition ratios of a binder, a disintegrant, a lubricant, an excipient or a mixture thereof determined in Examples 2-1 to 2-4, were prepared to evaluate the disintegration property. First, 75mg (15% (w/w) ) of a mixture (4:1, w/w) of amoxicillin and potassium clavulanate, magnesium stearate ("MgSA-1") , croscarmellose sodium("ccs-l") and copovidone ("co-pvp-1") were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 5mg(l%(w/w)) of silicon dioxide, magnesium stearate ("MgSA-2") , croscarmellose sodium("ccs-2") , copovidone ("co-pvp-2") and microcrystalline cellulose ("mcc") , mixed and compressed to prepare 500mg of a dispersible tablet formulation. In the course of preparing the dry-type granules and formulations, the composition ratios of each ingredients were varied as Table 6a below.

Table 6a: Composition Ratios of Each Ingredients Contained in Dispersible Tablet Formulations (unit : %,w/w)

Each of the dispersible tablet formulations comprising amoxicillin prepared as the above was disintegrated in 5mL of distilled water and the average disintegration time and particle size distribution were analyzed, respectively, where the control was the same as in Example 1 (see: Table 6b) .

Table 6b: Disintegration Time and Particle Size Distribution of Dispersible Tablet Formulations .

As shown in Table 6b above, it was clearly determined that the disintegration time differs in each of formulations and reaches to the level of 30 to 60% of control, while the particle sizes were finer than that of control . Accordingly, it could be concluded that a dispersible tablet formulation with dry-type granules comprising amoxicillin and a salt of clavulanic acid, a disintegrant, a binder, a lubricant and an excipient with the composition ratios determined in Examples 2-1 to 2-4 shows better disintegration property than that of prior art.

Example 4 : Preparation of Dispersible Tablet Formulations with Varied Composition Ratios of Amoxicillin

Dispersible tablet formulations comprising amoxicillin were prepared while changing the kinds of ingredients with the composition ratios of a binder, a disintegrant, a lubricant and an excipient of Exp. 8 showing the fastest disintegration in the formulations prepared in Example 3, and each of their disintegration property was measured, respectively. First, 15% (w/w) of a mixture (4:1, w/w) of amoxicillin and potassium clavulanate, 0.1% (w/w) of lubricant ("Al") , 10% (w/w) of disintegrant ("Bl") and 1% (w/w) of binder ("Cl") were mixed and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 1% (w/w) of silicon dioxide, 1% (w/w) of lubricant ("A2") , 10% (w/w) of disintegrant ("B2") , 1% (w/w) of binder ("C2") and 60.9% (w/w) of excipient ("D") , mixed and compressed to prepare 500mg of a dispersible tablet formulation. In the course of preparing the dry-type granules and formulations, the concrete ingredients of disintegrants, lubricants, binders and excipients were shown in Table 7a below.

Table 7a: The Details of Disintegrants, Lubricants, Binders and Excipients

*Abbreviation: cr-pvp, crospovidone; ccs, croscarmellos sodium; Na-stg, sodium starch glycolate; K-cmc, potassium carboxymethyl cellulose; pgst, pregelatinized starch; MgSA, magnesium stearate; tc, talc; PEG, polyethylene glycol; SA, stearic acid; co-pvp, copovidone; pvp, povidone; HPC, hydroxypropyl cellulose; HPMC, hydroxypropylmethyl cellulose; HEC, hydroxyethyl cellulose; mcc, microcrystalline cellulose; L-HPC, low substituted hydroxypropyl cellulose; LA, lactic acid; CHP, calcium hydrogen phosphate; cst, corn starch; Ma, mannitol.

The dispersible tablet formulations comprising amoxicillin prepared as the above were disintegrated in 5mL of distilled water, and the average disintegration time and particle size distribution (d90, d50 and dlO) were analyzed, respectively, where the control was the same as in Example Ksee: Table 7b) .

Table 7b: Disintegration Time and Particle Size Distribution of Dispersible Tablet Formulations

As shown in Table 7b above, the disintegration time showed no difference in each formulations, indicating that the disintegration was not affected by varying the kinds of disintegrants, lubricants, binders and excipients.

Example 5 : Preparation of Dispersible Tablet Formulations by Various Methods

Based on the results of Examples 3 and 4 demonstrating that a dispersible tablet formulation comprising amoxicillin, a binder, a disintegrant, a lubricant and an excipient with the composition ratios determined in Example 2 shows the same disintegration property, and the variation of ingredients does not have effect on the disintegration property, it was examined whether dispersible tablet formulations comprising amoxicillin prepared by various modified methods with the same ingredients and composition ratios of binder, disintegrant, lubricant and excipient show the similar disintegration property or not.

Example 5-1: Preparation of a Dispersible Tablet Formulation Comprising Amoxicillin by Employing Two Kinds of Dry-Type Granules First, 15% (w/w) of a mixture (4:1, w/w) of amoxicillin and potassium clavulanate, 0.1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium and 1% (w/w) of copovidone were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to obtain dry-type granules. Subsequently, to the dry-type granules were added 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, 1% (w/w) of copovidone and 60.9% (w/w) of microcrystalline cellulose, mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to obtain another dry-type granules. The said two dry-type granules were mixed with each other and compressed to prepare 500mg of a dispersible tablet formulation ("Exp. 1") Meanwhile, to prepare a dispersible tablet formulation as a control, 15% (w/w) of a mixture (4:1, w/w) of amoxicillin and potassium clavulanate, 0.1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium and 1% (w/w) of copovidone were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, 1% (w/w) of copovidone and 60.9% (w/w) of microcrystalline cellulose, mixed and compressed to prepare 500mg of a dispersible tablet formulation.

Example 5-2: Preparation of a Dispersible Tablet Formulation Containing Amoxicillin by Employing Dry-Type Granules and Wet-Type Granules First, 15% (w/w) of a mixture (4:1, w/w) of amoxicillin and potassium clavulanate, 0.1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium and 1% (w/w) of copovidone were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to obtain dry-type granules. Subsequently, to the dry-type granules were added 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, 1% (w/w) of copovidone and 60.9% (w/w) of microcrystalline cellulose, mixed with one another, and some distilled water and 1% (w/w) of copovidone were added in the mixture, and then subjected the said mixture to a series of processes of incorporation, granulation, drying and normalization to obtain wet-type granules. The dry-type granules and wet-type granules thus obtained by the above methods were mixed with each other and compressed to prepare 500mg of a dispersible tablet formulation ("Exp. 2"), where the control was the same as in Example 5-1.

Example 5-3: Preparation of a Dispersible Tablet Formulation Comprising Amoxicillin by Employing Wet-Type Granules and Dry-Type Granules

First, 12% (w/w) of amoxicillin, 0.1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium and 1% (w/w) of copovidone were mixed with one another, and some distilled water and 1% (w/w) of copovidone were added in the mixture, and then, subjected the said mixture to the processes of incorporation, granulation, drying and normalization to obtain wet-type granules. Subsequently, to the dry-type granules were added 3% (w/w) of clavulanic acid, 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, 1% (w/w) of copovidone and 60.9% (w/w) of microcrystalline cellulose, mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed 5 to lOrpm and screw speed of 5 to lOrpm, to obtain dry-type granules. The wet-type granules and dry-type granules thus obtained were mixed with each other and compressed to prepare 500mg of a dispersible tablet formulation ("Exp. 3"), where the control was the same as in Example 5-1.

Example 5-4 : Preparation of a Dispersible Tablet Formulation Containing Amoxicillin by Employing Two Kinds of Wet-Type Granules First, 12% (w/w) of amoxicillin, 0.1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, some distilled water and 1% (w/w) of copovidone were mixed with one another, and then, subjected to the processes of incorporation, granulation, drying and normalization to obtain wet-type granules. Subsequently, to the dry-type granules were added 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium and 60.9% (w/w) of microcrystalline cellulose, mixed with one another, and then some distilled water and 1% (w/w) of copovidone were added in the mixture to obtain wet-type granules similarly as the above. The two wet-type granules thus obtained were mixed with 3% (w/w) of clavulanic acid and compressed to prepare 500mg of a dispersible tablet formulation ("Exp. 4"), where the control was the same as in Example 5-1.

Example 5-5: Comparison of Disintegration Property Each of the dispersible tablet formulations of control and Exp. 1 to 4 prepared in Examples 5-1 to 5-4 was disintegrated in 5mL of distilled water and the average disintegration time and the particle size distribution (d90, d50 and dlO) were analyzed by the method described in Example 1, respectively (see: Table 8)

Table 8: The Disintegration Time and Particle Size Distribution of Dispersible Tablet Formulations

As shown in Table 8 above, the dispersible tablet formulations with dry-type granules comprising amoxicillin and a salt of clavulanic acid(i.e., Exp. 1 and 2) showed disintegration property equal to the control, while those with wet-type granules comprising amoxicillin (i.e. , Exp. 3 and 4) did considerably increased disintegration time and decreased dispersion property, indicating that they possess a disintegration property similar to that of formulation disclosed in PCT international publication WO 04/06917. Accordingly, it could be concluded that: to prepare the dispersible tablet formulation of present invention showing the excellent disintegration property, the dry-type granules comprising amoxicillin and a salt of clavulanic acid should be employed, while the subsequent processes may be varied.

Example 6: Preparation of Dispersible Tablet Formulation Comprising Amoxicillin and Foaming Agent

Based on the knowledge that a foaming agent affects the disintegration time and dispersion property along with disintegrant and binder, the effect of foaming agent on the disintegration property of the dispersible tablet formulation of present invention was examined.

Example 6-1: Preparation of Dispersible Tablet Formulation Comprising Amoxicillin and Foaming Agent

First, 15% (w/w) of a mixture (4:1, w/w) of amoxicillin and potassium clavulanate, 0.1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, 2% (w/w) of citric acid, 2% (w/w) of sodium hydrogen carbonate and 1% (w/w) of copovidone were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, 1% (w/w) of copovidone, 2% (w/w) of citric acid, 2% (w/w) of sodium hydrogen carbonate and 72.9% (w/w) of microcrystalline cellulose, mixed and compressed to prepare 500mg of a dispersible tablet formulation ("Exp. ") . Meanwhile, as a control, 15% (w/w) of a mixture (4:1, w/w) of amoxicillin and potassium clavulanate, 0.1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium and 1% (w/w) of copovidone were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, 1% (w/w) of copovidone and 60.9% (w/w) of microcrystalline cellulose, mixed and compressed to prepare 500mg of a dispersible tablet formulation.

Each of the dispersible tablet formulations of Exp. and control was disintegrated in 5mL of distilled water, and the average disintegration time and the particle size distribution (d90, d50 and dlO) were analyzed by the method described in Example 1, respectively (see: Table 9a)

Table 9a: Disintegration Time and Particle Size Distribution of Dispersible Tablet Formulations

As shown in Table 9a above, a dispersible tablet formulation comprising a foaming agent (i.e., Exp.), when compared with the control, had no difference in dispersion property though it showed a considerably reduced disintegration time.

Example 6-2 : Determination of Optimized Composition Ratio of Foaming Agent

Based on the results in Example 6-1 showing that a foaming agent promotes disintegration of dispersible tablet formulation, the composition ratio of foaming agent showing the most excellent disintegration property was determined by the following experiments.

First, 15% (w/w) of a mixture (4:1, w/w) of amoxicillin and potassium clavulanate, 0.1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, a foaming agent (a mixture 1:1 (w/w) of citric acid powder and sodium hydrogen carbonate) and 1% (w/w) of copovidone were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, 1% (w/w) of copovidone, a foaming agent and microcrystalline cellulose, mixed and compressed to prepare 500mg of a dispersible tablet formulation. In the course of preparing the dry-type granules and formulations, the composition ratios of foaming agent ("SHC") and microcrystalline cellulose ("mcc") as an excipient were varied as followings, to prepare each of the dispersible tablet formulations containing a foaming agent at a ratio of 0 to 15%, and measured the disintegration time by the method described in Example 1, respectively (see: Table 9b): 60.9% (w/w) mmcccc;; l%(w/w) SHC,

59.9% (w/w) mcc; 2% (w/w) SHC, 58 9% (w/w) mmcccc;; 3% (w/w) SHC,

57.9% (w/w) mcc; 4% (w/w) SHC, 56 9% (w/w) mmcccc;; 5% (w/w) SHC,

55.9% (w/w) mcc; 6% (w/w) SHC, 54 9% (w/w) ramccec;; 7% (w/w) SHC,

53.9% (w/w) mcc; 8% (w/w) SHC, 52 9% (w/w) mmcccc;; 9% (w/w) SHC,

51.9% (w/w) mcc; 10% (w/w) SHC, 50.9% (w/w) mcc; 11% (w/w) SHC,

49.9% (w/w) mcc; 12% (w/w) SHC, 48.9% (w/w) mcc; 13% (w/w) SHC,

47.9% (w/w) mcc; 14% (w/w) SHC, 46.9% (w/w) mcc; and, 15% (w/w)

SHC, 45.9% (w/w) mcc.

Table 9b: Effects of Composition Ratio of Foaming Agent on Disintegration Time

As shown in Table 9b above, a dispersible tablet formulation comprising a foaming agent was disintegrated faster than that of foaming agent-free formulation. Especially, the disintegration time decreased sharply with the addition of above 2% (w/w) foaming agent, and no more decrease was not examined with the addition of above 10% (w/w) .

Example 6-3: Preparation of Dispersible Tablet Formulations Comprising Amoxicillin with Various Composition Ratios

Within the range of each of composition ratios determined in Example 6-2, dispersible tablet formulations comprising amoxicillin were prepared while varying the composition ratio of a foaming agent, and the disintegration property of each of formulations was examined, respectively. First, 15% (w/w) of a mixture (4:1, w/w) of amoxicillin and potassium clavulanate, 0.1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, a foaming agent (a mixture of citric acid powder and sodium hydrogen carbonate in a ratio of 1:1 (w/w)) ("Al") and 1% (w/w) of copovidone were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose sodium, 1% (w/w) of copovidone, a foaming agent ("A2") and microcrystalline cellulose ("B") , mixed and compressed to prepare 500mg of a dispersible tablet formulation, where the composition ratios of foaming agents (Al, A2) and microcrystalline cellulose (B) were shown in Table 9c below.

Table 9c: Composition Ratios of Foaming Agent and Microcrystalline Cellulose (unit : w/w)

The compositions of Al and A2 are the same as each other,

Each of the dispersible tablet formulations comprising amoxicillin was disintegrated in 5mL of distilled water and the average disintegration time and the particle size distribution (d90, d50, dlO) were analyzed, respectively, where the control was the same as in Example 1 (see: Table 9d) .

Table 9d: Disintegration Time and Particle Size Distribution of Dispersible Tablet Formulations

As shown in Table 9d above, the disintegration time was not dependent on the time of adding a foaming agent, while the disintegration time was changed dependent on the composition ratio of a foaming agent.

Example 7 : Preparation of Dispersible Tablet Formulations Comprising Various Beta-Lactam Antibiotics and Evaluation of Disintegration Property

Dispersible tablet formulations comprising beta lactam antibiotics such as penicillin or pivampicillin other than amoxicillin were prepared and the disintegration time and the particle size distribution (d90, d50 and dlO) of the said formulations were analyzed, respectively.

Example 7-1: Preparation of a Dispersible Tablet Formulation Comprising Penicillin and Evaluation of Disintegration Property

188mg of a mixture (2:1, w/w) of penicillin and potassium clavulanate, 30mg of crospovidone, 8mg of copovidone, 23mg of silicon dioxide, 8mg of magnesium stearate, 9mg of citric acid and llmg of sodium hydrogen carbonate were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 15mg of low substituted hydroxypropyl cellulose, 145mg of microcrystalline cellulose, 47mg of crospovidone, 9mg of magnesium stearate and 7mg of povidone, mixed and compressed to prepare 500mg of a dispersible tablet formulation and the average disintegration time and the particle size distribution (d90, d50 and dlO) of the formulations were analyzed, respectively (see: Table 10a).

Table 10a: Disintegration Time and Particle Size Distribution of a Dispersible Tablet Formulation Comprising Penicillin

Ave. Disint. Time 35

Example 7-2: Preparation of a Dispersible Tablet Formulation Comprising Pivampicillin and Evaluation of Disintegration Property

156mg of a mixture (4:1, w/w) of pivampicillin and potassium clavulanate, 48mg of crospovidone, 9mg of copovidone, 25mg of silicon dioxide, 7mg of magnesium stearate, 9mg of citric acid and llmg of sodium hydrogen carbonate were mixed with one another and compressed by subjecting the mixture to a roller compactor which runs at a roller speed of 5 to lOrpm and screw speed of 5 to lOrpm, to give dry-type granules. Subsequently, to the dry-type granules were added 113mg of microcrystalline cellulose, 60mg of lactic acid, 42mg of crospovidone, 12mg of magnesium stearate and 8mg of povidone, mixed and compressed to prepare 500mg of a dispersible tablet formulation and the average disintegration time and the particle size distribution (d90, d50 and dlO) of the formulations were analyzed, respectively (see: Table 10b).

Table 10b: Disintegration Time and Particle Size Distribution of a Dispersible Tablet Formulation Comprising Pivampicillin

As shown in the results of Examples 7-1 and 7-2, it was clearly determined that the process for preparing a dispersible tablet formulation of present invention can also comprise a variety of beta lactam antibiotics such as penicillin or pivampicillin besides amoxicillin, and the formulation prepared by the process can reduce the average disintegration time and show the excellent dispersion property, which indicates that the invented process can be practically applied in the formulation of various beta lactam antibiotics.

Usage

The dispersible tablet formulation comprising beta lactam antibiotics of present invention may be administered at a concentration of 20 to 50mg/mL (dispersed in water) in a dose of 5 to 20mg per body weight (kg), which can be varied dependent on the patient's age, gender, symptoms, way of administration or the purpose of prevention. For a patient showing specific symptoms, those skilled in the art can vary the individual dose according to the patient's body weight, age, gender, health condition, diet, time of administration, way of administration, rate of excretion, severity of disease, etc.

As clearly explained and demonstrated as the above, the present invention provides a dispersible tablet formulation comprising beta lactam antibiotics in which a beta lactam antibiotic is formulated with a salt of clavulanic acid in a tablet form to be easily administered upon the disintegration in water, and a process for preparing the same. The dispersible tablet formulation of the present invention can be practically applied for the treatment of diseases requiring beta lactam antibiotics, since it can be easily taken by the infants or older patients being troubled with oral administration with improved disintegration rate and dispersion property.

It will be understood that the above description is merely illustrative of the preferred embodiment and it is not intended to limit the scope of the invention to the particular forms set forth, but on the contrary, it is intended to cover such alternatives, modifications and equivalents as may be included within the spirit and scope of the invention as defined by the claims.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a dispersible tablet formulation comprising beta lactam antibiotics which comprises the steps of: (i) mixing a beta lactam antibiotic and a salt of clavulanic acid with a disintegrant, a lubricant and a binder, and then applying the mixture to a roller compactor to obtain dry-type granules; and, (ii) mixing the dry-type granules obtained in step(i) with an excipient, a disintegrant, a lubricant and a binder, and compressing the mixture to give a dispersible tablet.

2. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the beta lactam antibiotic is penicillin antibiotic.

3. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 2, wherein the penicillin antibiotic is penicillin, amoxicillin, ampicillin, ciclacillin, epicillin, phenethicillin or pivampicillin.

4. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the salt of clavulanic acid is potassium clavulanate.

5. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the mixture of a beta lactam antibiotic and a salt of clavulanic acid of step(i) is included in the dispersible tablet formulation at a ratio of 15 to 40% (w/w).

6. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the disintegrant of step(i) is crospovidone, croscarmellose sodium, sodium starch glycolate, potassium carboxymethyl cellulose, pregelatinized starch or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 3 to 10% (w/w) .

7. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the lubricant of step(i) is magnesium stearate, silicon dioxide, talc, polyethylene glycol, stearic acid or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 0.1 to 5% (w/w) .

8. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the binder of step(i) is copovidone, povidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 0.1 to 7.5% (w/w) .

9. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein a desiccant or a foaming agent is further added to the mixture of a beta lactam antibiotic and a salt of clavulanic acid, a disintegrant, a lubricant and a binder during a process of step(i).

10. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 9, wherein the desiccant is silicon dioxide, synthetic aluminium silicate, light anhydrous silicic acid or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 0.1 to 10% (w/w) .

11. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 9, wherein the foaming agent is citric acid, tartaric acid, alginic acid, malic acid, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 1 to 5% (w/w).

12. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the excipient of step(ii) is microcrystalline cellulose, low substituted hydroxypropyl cellulose, lactose, calcium hydrogen phosphate, corn starch, mannitol, sorbitol, xylitol or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 30 to 75% (w/w).

13. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the disintegrant of step(ii) is crospovidone, croscarmellose sodium, sodium starch glycolate, potassium carboxymethyl cellulose, pregelatinized starch or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 3 to 10% (w/w).

14. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the lubricant of step(ii) is magnesium stearate, silicon dioxide, talc, polyethylene glycol, stearic acid or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 0.1 to 5% (w/w) .

15. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the binder of step(ii) is copovidone, povidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 0.1 to 7.5% (w/w) .

16. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the excipient, disintegrant, lubricant and binder of step(ii) are mixed with dry-type granules obtained in step(i), in a form of powder.

17. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the excipient, disintegrant, lubricant and binder in step(ii) are mixed with the dry-type granules obtained in step(i), in a form of dry-type granules obtained by mixing and compressing those materials.

18. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein the excipient, disintegrant, lubricant and binder of step(ii) are mixed with dry-type granules obtained in step(i), in a form of wet-type granules obtained by mixing those materials with water.

19. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 1, wherein a foaming agent is further added in the mixture of dry-type granules obtained in step(i) and an excipient, a disintegrant, a lubricant and a binder during a process of step (ii) .

20. The process for preparing a dispersible tablet formulation comprising beta lactam antibiotics of claim 19, wherein the foaming agent is citric acid, tartaric acid, alginic acid, malic acid, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 1 to 5% (w/w) .

21. A dispersible tablet formulation comprising beta lactam antibiotics prepared by claim 1, which comprises an active ingredient of a mixture of a beta lactam antibiotic and a salt of clavulanic acid 15 to 40% (w/w), a disintegrant 6 to 20% (w/w), a lubricant 0.1 to 10% (w/w) , a binder 0.1 to 15% (w/w), an excipient 30 to 75% (w/w) of the dispersible tablet formulation.

22. The dispersible tablet formulation comprising beta lactam antibiotics of claim 21, wherein the beta lactam antibiotic is penicillin antibiotic.

23. The dispersible tablet formulation comprising beta lactam antibiotics of claim 22, wherein the penicillin antibiotic is penicillin, amoxicillin, ampicillin, ciclacillin, epicillin, phenethicillin or pivampicillin.

24. The dispersible tablet formulation comprising beta lactam antibiotics of claim 21, wherein the salt of clavulanic acid is potassium clavulanate.

25. The dispersible tablet formulation comprising beta lactam antibiotics of claim 21, wherein the disintegrant is crospovidone, croscarmellose sodium, sodium starch glycolate, potassium carboxymethyl cellulose, pregelatinized starch or a mixture thereof.

26. The dispersible tablet formulation comprising beta lactam antibiotics of claim 21, wherein the lubricant is magnesium stearate, silicon dioxide, talc, polyethylene glycol, stearic acid or a mixture thereof.

27. The dispersible tablet formulation comprising beta lactam antibiotics of claim 21, wherein the binder is copovidone, povidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose or a mixture thereof.

28. The dispersible tablet formulation comprising beta lactam antibiotics of claim 21, wherein the excipient is microcrystalline cellulose, low substituted hydroxypropyl cellulose, lactose, calcium hydrogen phosphate, corn starch, mannitol, sorbitol, xylitol or a mixture thereof.

29. The dispersible tablet formulation comprising beta lactam antibiotics of claim 21, wherein a foaming agent, a desiccant or a mixture thereof is further included in the dispersible tablet formulation.

30. The dispersible tablet formulation comprising beta lactam antibiotics of claim 29, wherein the foaming agent is citric acid, tartaric acid, alginic acid, malic acid, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 2 to 10% (w/w) .

31. The dispersible tablet formulation comprising beta lactam antibiotics of claim 29, wherein the desiccant is silicon dioxide, synthetic aluminium silicate, light anhydrous silicic acid or a mixture thereof, and included in the dispersible tablet formulation at a ratio of 0.1 to 10% (w/w) .

32. A dispersible tablet formulation comprising amoxicillin which comprises a mixture of amoxicillin and a salt of clavulanic acid (4:1, w/w) 15 to 40% (w/w), a disintegrant 6 to 20% (w/w) , a lubricant 0.1 to 10% (w/w) , a binder 0.1 to 15% (w/w) , an excipient 30 to 75% (w/w) , a foaming agent 2 to 10% (w/w) and a desiccant 0.1 to 10% (w/w) of the dispersible tablet formulation.