CN1767818A - Dispersible tablet comprising beta lactam antibiotics and process for preparing the same - Google Patents

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 containing β-lactam antibiotic and its preparation method

Background of the invention

technical field

The present invention relates to a dispersible tablet containing a β-lactam antibiotic and a method for preparing the same, more particularly, the present invention relates to a dispersible tablet containing a β-lactam antibiotic, wherein the β-lactam antibiotic is formulated with clavulanate Tablet form, which is easy to take when disintegrated in water, and a process for the preparation of such dispersible tablets.

Background technique

Amoxicillin, a beta-lactam antibiotic, is also known as semi-synthetic penicillin or broad-spectrum penicillin and is most widely used as an antibiotic drug for the treatment of sore throat or tonsillitis. Due to the frequent use of amoxicillin, amoxicillin-resistant strains with β-lactamase activity have become popular. Therefore, amoxicillin is formulated as a combination with clavulanate, which inhibits β-lactamase activity. Among the most frequently used formulations, amoxicillin is mixed with potassium clavulanate in a 2:1 (w/w) ratio, co-amoxiclav formulations are commercially available under the trademark Augmentin ^™ , It is prepared in the form of film-coated tablet, dry syrup, etc.

The clavulanate contained in the preparation is very sensitive to humidity, and a small amount of water can easily cause decomposition, so in this field, various studies have been conducted on this problem. For example, US Pat. No. 6,051,255 discloses a tablet that prevents external moisture from contacting clavulanate by film coating a compressed mixture of amoxicillin and clavulanate. Such film-coated tablets pose no particular problem for adults, but have trouble with oral administration to infants or elderly people who do not like to swallow because of the feeling of foreign matter.

As an option to overcome the problems posed by said film-coated tablets, various types of formulations were prepared in which amoxicillin and clavulanate were not formulated in tablets and administered to infants or elderly patients . For example, WO 01/45667 discloses water soluble powders or granules comprising amoxicillin trihydrate and clavulanate. However, the water soluble powders or granules are formulated to absorb water easily, which allows direct or indirect contact of the unpackaged formulation with water, eventually breaking down the clavulanate and gradually reducing the potency of the unused drug over time. In order to overcome said problem, attempts were made to slow down the decomposition by freezing the unpackaged preparations, but ultimately this did not solve the problem. Furthermore, said methods allow the frozen stored unpackaged formulation to partially freeze or recrystallize absorbed water so that the patient does not receive an effective amount.

Furthermore, WO 00/03695 discloses liquid aqueous pharmaceutical suspension formulations containing amoxicillin trihydrate, clavulanate and cellulose as filler. Dry syrups are prepared by adding sweeteners to suspension formulations, which are currently sold in large quantities as antibiotic formulations containing amoxicillin and clavulanate. However, suspension preparations including dry syrups are too hygroscopic and not resistant to moisture, and there is a problem that clavulanate is easily decomposed or changes in potency due to long-term storage.

As an alternative to overcome the aforementioned drawbacks of water-soluble powders, granules and suspensions, a dispersible tablet, in which amoxicillin and clavulanate are formulated, is administered to infants or elderly patients. For example, WO 04/06917 discloses dispersible tablets prepared by mixing and compressing amoxicillin and croscarmellose sodium as a disintegrant to obtain granules to which potassium clavulanate is added , croscarmellose sodium as a disintegrant, silicon dioxide as a desiccant, microcrystalline cellulose as an excipient, magnesium stearate as a lubricant, flavoring, sweetener and food coloring mixture, and then compress the mixture. However, the dispersible tablet causes some inconvenience during administration, such as even though it does not contain a binder to improve dispersibility, it still takes more than 2 minutes to disintegrate in water, and due to relatively large disintegrating particles , some patients may experience a foreign body sensation.

In order to solve the above-mentioned problems, various studies have been conducted in this field, but no successful cases have been seen so far.

Under such circumstances, there is a strong need to develop a dispersible tablet containing amoxicillin and clavulanate which can be administered simply and easily with improved disintegration rate and dispersibility.

Contents of the invention

The inventors have worked hard to develop a dispersible tablet containing amoxicillin and clavulanate, which can be administered simply and easily, and the inventors have found that the desired dispersible tablet can be prepared as follows: - Lactam antibiotics and clavulanate are mixed with disintegrants, lubricants and binders, and then the mixture is fed into a roller compactor to obtain dry granules; then, the The dry granules are mixed with excipients, disintegrants, lubricants and binders, and the mixture is compressed to obtain tablets. They also demonstrated that the dispersible tablet could actually be used to treat diseases that require beta-lactam antibiotics, as it can be easily administered by infants or elderly patients who have difficulty oral administration.

Accordingly, the main object of the present invention is to provide a process for the preparation of dispersible tablets containing β-lactam antibiotics, which have improved disintegration rate and dispersibility.

Another object of the present invention is to provide dispersible tablets containing β-lactam antibiotics prepared by said method.

Detailed description of the invention

The method for preparing dispersible tablets containing β-lactam antibiotics comprises the steps of: (i) mixing β-lactam antibiotics and clavulanate with disintegrants, lubricants and binding agents, and then sending the mixture to into a roller press to obtain dry granules; then, (ii) mix said dry granules with excipients, disintegrants, lubricants and binders, and compress the mixture to obtain tablets. In the practice of the present invention, the β-lactam antibiotics are not limited, but are preferably penicillin antibiotics, more preferably penicillin (penicillin), amoxicillin (amoxicillin), ampicillin (ampicillin), cyclohexicillin ( ciclacillin), epicillin, phenethicillin or pivampicillin, the clavulanate is not limited, but clavulanate potassium is preferred.

As described in the previous prior art, the β-lactam antibiotic and clavulanate are preferably mixed in a ratio of 2:1 to 14:1 (w/w), most preferably in a ratio of 4:1 (w/w). The content of the mixture of beta-lactam antibiotic and clavulanate in the tablet is 15-40% (w/w).

In addition, the disintegrant in step (i) is not limited, but preferably crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose potassium, pregelatinized starch or a mixture thereof, in a dispersible tablet, the content of the disintegrant is not limited, but preferably 3-10% (w/w).

The lubricant in step (i) is not limited, but is preferably magnesium stearate, silicon dioxide, talc, polyethylene glycol, stearic acid or mixtures thereof, in dispersible tablets, the content of said lubricant is not Limited, but preferably 0.1-5% (w/w). The binder in step (i) is not limited, but is preferably copovidone, povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose or Mixtures, in dispersible tablets, the content of the binder is not limited, but preferably 0.1-7.5% (w/w).

In addition, in step (i), desiccant or foaming agent can be further added to the mixture of β-lactam antibiotic and clavulanate together with disintegrant, lubricant and binder, wherein said The desiccant is not limited, but it is preferably silicon dioxide, synthetic aluminum silicate, light anhydrous silicic acid or a mixture thereof. In the dispersible tablet, the content of the desiccant is not limited, but usually preferably 0.1-10% (w/w). The foaming agent is not limited, but is preferably citric acid, tartaric acid, alginic acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or a mixture thereof. In a dispersible tablet, the foaming agent The foaming agent content is not limited, but is preferably 1-5% (w/w).

Meanwhile, the excipient of step (ii) is not limited, but is preferably microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, calcium hydrogen phosphate, corn starch, mannitol, sorbitol, xylitol or The mixture thereof, in the dispersible tablet, the content of said excipient is not limited, but preferably 30-75% (w/w). The disintegrant in step (ii) is not limited, but preferably crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose potassium, pregelatinized starch or a mixture thereof, in In the dispersible tablet, the content of the disintegrant used in step (ii) is not limited, but preferably 3-10% (w/w). The lubricant in step (ii) is not limited, but is preferably magnesium stearate, silicon dioxide, talc, polyethylene glycol, stearic acid or a mixture thereof, in dispersible tablets, used in step (ii) The lubricant content is not limited, but is preferably 0.1-5% (w/w). The binding agent in step (ii) is not limited, but preferably copovidone, povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose or mixture thereof, in dispersible tablet In, the content of the binder in the step (ii) is not limited, but is preferably 0.1-7.5% (w/w).

In addition, in step (ii), the excipients, disintegrants, lubricants and binders are mixed with the dry granules obtained in step (i) in one of the following forms: powder form, by mixing and dry granular forms obtained by compressing these materials; and wet granular forms obtained by mixing these materials with water.

Finally, in step (ii), a foaming agent may be further added to the dry granules obtained in step (i) together with excipients, disintegrants, lubricants and binders. In this step, the foaming agent is not limited, but is preferably citric acid, tartaric acid, alginic acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or a mixture thereof, in dispersible tablets , the content of blowing agent used in step (ii) is not limited, but preferably 1-5% (w/w).

In order to develop a compound preparation of amoxicillin and clavulanate that can be taken by infants or elderly patients who have difficulty in oral administration, the present inventors have made various efforts and noticed the dispersible tablet disclosed in WO04/06917, Wet granules containing amoxicillin are mixed with clavulanate and compressed to give orodispersible tablets that disperse in water.

The present inventors tried to improve the disintegration rate and dispersibility of dispersible tablets by changing the components and the composition ratio of the components; dry granules of mixture; and optimizing the composition ratio of disintegrant, lubricant and binder, and foaming agent as an optional component.

Typically, lubricants and binders should be used to prepare dry granules, wherein the binders facilitate the bonding of the components. Naturally, the inventors expected that a dispersible tablet using dry granules of a mixture of amoxicillin and clavulanate would have a lower disintegration rate than the dispersible tablet of WO 04/06917, however, contrary to expectations, the present The inventive formulation exhibits a high disintegration rate and excellent dispersibility.

The present inventors prepared various dispersible tablets using dry granules of amoxicillin and clavulanate, optimized the compositional ratio of disintegrants, lubricants, binders and excipients, and determined each Disintegration time and dispersibility of formulations. The results showed that all the various dispersible tablets using dry granules exhibited higher disintegration rates and improved dispersibility compared to the dispersible tablets of WO 04/06917, especially the dispersible tablets containing effervescent agents Formulations exhibited faster disintegration rates than formulations without foaming agents. Therefore, it can be concluded that the dispersible tablet of the present invention is more therapeutically effective than the prior art formulations by using dry granules for simple administration and easy absorption by the body.

At the same time, the inventors found that a lubricant should be included in the two steps of obtaining dry granules and compressing the mixture containing said dry granules to obtain dispersible tablets, that is, adding β-lactam antibiotics, clavulanate During the process of feeding the mixture of acid salt, disintegrant, lubricant and binder into the roller compactor to obtain dry granules, said lubricant prevents the mixture from adhering to the roller compactor, which would otherwise hinder the Continuous process for dry pellets. In addition, the use of a lubricant also prevents the mixture from sticking to the punches of the compressor during the subsequent process of compressing the mixture of dry granules, excipients, disintegrants, lubricants and binders to obtain tablets, Otherwise the continuous compression process will be hindered. Therefore, it has been confirmed that a lubricant should be included both in the step of obtaining dry granules and in the step of compressing the mixture to prepare dispersible tablets.

As mentioned above, the dispersible tablet of the present invention is inherently prepared to contain amoxicillin. However, considering that it is designed to use clavulanate that inhibits β-lactamase of amoxicillin-resistant bacteria, the preparation of the present invention can include various drugs, which can be used as a clavulanate-containing compound preparation. For example, the compound preparation mixed with clavulanate and β-lactam antibiotics such as ampicillin, penicillin, cyclohexicillin, epicillin, phenicillin, pampicillin is prepared into the dispersible tablet form of the present invention, so the The dispersible tablet described above can overcome drug resistance to β-lactam antibiotics, and has improved disintegration rate and dispersibility, ensuring simple and easy administration and absorption. In order to prove this expectation, penicillin and paminecillin were respectively mixed with clavulanate potassium, each dispersible tablet prepared by the above method was disintegrated in water, and the disintegration time was measured. As a result, all the dispersible tablets were completely disintegrated within 30-40 seconds, indicating that the dispersible tablet of the present invention can be applied to various β-lactam antibiotics and amoxicillin.

The thus prepared dispersible tablets containing β-lactam antibiotics comprise 15-40% (w/w) of a mixture of β-lactam antibiotics and clavulanate as active ingredients, and 6-20% (w/w) /w) disintegrant, 0.1-10% (w/w) lubricant, 0.1-15% (w/w) binder, 30-75% (w/w) excipient, and Optional foaming agent, desiccant or mixture thereof, preferably the content of desiccant is 0.1-10% (w/w), and the content of foaming agent is 2-10% (w/w).

The dispersible tablet can be practically used for the treatment of diseases requiring β-lactam antibiotics because it has improved disintegration rate and dispersibility and can be easily orally administered by infants or elderly patients who have difficulty in oral administration.

The present invention is described in more detail in the following examples, but these examples should not be construed as limiting the scope of the present invention.

Embodiment 1 : the preparation of the dispersible tablet containing amoxicillin and the evaluation of disintegration performance

First, dispersible tablets were prepared by using wet granules disclosed in PCT International Publication WO 04/06917: 231.0 g of amoxicillin, 12.5 mg of croscarmellose sodium, 0.5 mg of coloring matter, and some water were mixed to obtain wet granules . Then, 104.4 mg of potassium clavulanate, 12.5 mg of croscarmellose sodium, 20 mg of fragrance, 0.5 mg of pigment, 5 mg of silicon dioxide, 10 mg of aspartame, and 10 mg of aspartame were added to the wet granules thus obtained. 200 mg of microcrystalline cellulose and 7.5 mg of magnesium stearate were mixed and compressed to obtain 600 mg of dispersible tablets.

Then, another dispersible tablet was prepared similarly as above except using dry granules instead of wet granules, wherein said dry granules were prepared by a binder: that is, 231.0 g of amoxicillin, 104.4 mg potassium clavulanate, 12.5 mg croscarmellose sodium, 3.5 mg magnesium stearate, 0.5 mg pigment and 3 mg copovidone were mixed with each other, with a roller speed of 5-10 rpm and a screw speed of 5-10 rpm. The roller compactor compresses the mixture to obtain dry granules. Subsequently, 12.5 mg of croscarmellose sodium, 14 mg of spices, 0.5 mg of pigment, 3 mg of copovidone, 5 mg of silicon dioxide, 10 mg of aspartame, and 200 mg of microcrystalline cellulose were added to the dry granules. and 4.0 mg magnesium stearate, mixed, compressed to obtain 600 mg dispersible tablets.

Each dispersible tablet prepared by the two methods was disintegrated in 5ml of distilled water, and the time required for the particle size to reach below 200 mesh was measured by naked eyes, measured 10 times, and the average disintegration time was calculated, and then by automatic The particle size analyzer determines the particle size distribution of the disintegrated particles ( see : Table 1).

Table 1 : Disintegration properties of dispersible tablets prepared using dry granules and wet granules as intermediates Intermediate type Average disintegration time (seconds) d90(μm) d50(μm) d10(μm) Wet Granules 125 118.4 39.2 9.8 Dry Granules 93 87.4 21.7 6.4

As mentioned in Table 1 above, it is clearly shown that dispersible tablets prepared by using dry granules disintegrate faster than dispersible tablets prepared by using wet granules. These results are contrary to what we expected: dispersible tablets prepared by using dry granules will disintegrate faster than those prepared by using wet granules because binders such as copovidone are usually used to bind each components to obtain difficult disintegration properties. In addition, it was also shown that dispersible tablets prepared by using dry granules had a finer particle size after disintegration in water than dispersible tablets prepared by using wet granules.

Therefore, it can be concluded that the results are caused by the two factors of different intermediates (i.e. dry and wet granules) and different preparation methods of the formulations because: Each formulation was prepared using different intermediates except that the binder was added in dry granules by reducing the amount of the same flavor which had no effect on the disintegration rate.

During the preparation of dispersible tablets with dry granules, since disintegrants and binders may have a critical influence on disintegration properties such as disintegration rate and dispersibility, the disintegrants and binders that showed the best disintegration properties were determined. Whether the binder ratio, lubricant to excipient ratio has an effect on the disintegration performance is also demonstrated in the following examples.

Embodiment 2 : Optimizing the composition ratio of each component contained in the dispersible tablet

In the dispersible tablet using the dry granules prepared in Example 1 as an intermediate, each composition of disintegrant, binder, lubricant and excipient to obtain the best disintegration rate and dispersibility was measured respectively Compare.

Embodiment 2-1 : Determining the optimal composition ratio of disintegrant

120 mg of amoxicillin, 30 mg of potassium clavulanate, 5 mg of magnesium stearate, croscarmellose sodium and 2 mg of copovidone were mixed with each other, and then the mixture was fed into the roller with a speed of 5-10 rpm and a screw speed of 5 Compression was performed in a roller press at -10 rpm to obtain dry granules. Subsequently, croscarmellose sodium, 5 mg silicon dioxide, 3 mg copovidone, microcrystalline cellulose and 5 mg magnesium stearate were added to the dry granules, mixed and compressed to obtain 500 mg dispersible tablets , The disintegration time of each formulation was measured by the same method as in Example 1 ( see : Table 2a). During the preparation of dry granules and formulations, the amount of croscarmellose sodium (ccs) as a disintegrant and the amount of microcrystalline cellulose (mcc) as an excipient were varied as follows in order to Tablets contain 0, 5, 10, 15, 20, 25 or 30% (w/w) of disintegrants: 0mg ccs, 330mg mcc; 25mg ccs, 305mg mcc; 50mg ccs, 280mg mcc; 75mg ccs, 255mg mcc; 100mg ccs, 230mgmcc; 125mg ccs, 205mg mcc; and 150mg ccs, 180mg mcc.

Table 2a : Effect of composition ratio of disintegrants on disintegration time Composition ratio of disintegrant (%, w/w) Disintegration time (seconds) 0 300 5 180 10 70 15 57 20 45 25 45 30 45

As shown in Table 2a above, in the range of more than 10% (w/w) of disintegrant, the disintegration time decreases sharply, and in the range of more than 20% (w/w), the disintegration time does not decrease any more. In order to determine the composition ratio of the disintegrant more accurately, each disintegrant was prepared with a disintegrant content of 5, 6, 7, 8, 9, 10, 15, 16, 17, 18, 19 or 20% (w/w). The tablets were dispersed and the disintegration time determined ( see : Table 2b).

Table 2b : Effect of composition ratio of disintegrants on disintegration time Composition ratio of disintegrant (%, w/w) Disintegration time (seconds) 5 180 6 90 7 83 8 76 9 72 10 70 15 57 16 54 17 51 18 48 19 46 20 45

As shown in Table 2b above, when the disintegrant is greater than 6% (w/w), the disintegration time decreases sharply, and when the disintegrant is greater than 20% (w/w), the disintegration time does not decrease any more.

Embodiment 2-2 : determine the optimal composition ratio of binder

120 mg of amoxicillin, 30 mg of potassium clavulanate, 5 mg of magnesium stearate, 20 mg of croscarmellose sodium and copovidone were mixed with each other, and then the mixture was fed into the roller with a speed of 5-10 rpm and a screw speed of 5 Compression was performed in a roller press at -10 rpm to obtain dry granules. Subsequently, 20 mg of croscarmellose sodium, 5 mg of silicon dioxide, copovidone, microcrystalline cellulose and 5 mg of magnesium stearate were added to the dry granules, mixed and compressed to obtain 500 mg of dispersible tablets , The disintegration time of each formulation was measured by the same method as in Example 1 ( see : Table 3a). During the preparation of dry granules and formulations, the amount of copovidone ("co-pvp") as a binder and the amount of microcrystalline cellulose ("mcc") as an excipient were varied as follows in order to prepare Dispersible tablets containing 0, 3, 6, 9, 12, 15 or 18% (w/w) disintegrants: 0mg 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, 220mg mcc; and 90mg co-pvp, 205mg mcc.

Table 3a : The effect of the composition ratio of the binder on the disintegration time Binder composition ratio (%, w/w) Disintegration time (seconds) 0 - 3 39 6 40 9 41 12 43 15 44 18 73

As shown in Table 3a above, dry granules could not be prepared properly and disintegration times could not be measured in cases where no binder was added, and in cases where binder was added above 15% (w/w) , the disintegration time increases dramatically. In order to determine the composition ratio of the binder more accurately, dispersible tablets were prepared with binder contents of 15, 16, 17 or 18% (w/w), and the disintegration times were measured respectively ( see : Table 3b).

Table 3b : The effect of the composition ratio of the binder on the disintegration time Binder composition ratio (%, w/w) Disintegration time (seconds) 15 44 16 58 17 66 18 73

As shown in Table 3b above, in the range of more than 16% (w/w) of binder, the disintegration time increases sharply, indicating that the binder composition ratio below 15% (w/w) is preferred.

Embodiment 2-3 : determine the optimum composition ratio of lubricant

120 mg of amoxicillin, 30 mg of potassium clavulanate, 50 mg of croscarmellose sodium, 40 mg of copovidone and magnesium stearate were mixed with each other, and then the mixture was fed into the roller with a speed of 5-10 rpm and a screw speed of 5 Compression was performed in a roller press at -10 rpm to obtain dry granules. Subsequently, 50 mg of croscarmellose sodium, 5 mg of silicon dioxide, 35 mg of copovidone, microcrystalline cellulose and magnesium stearate were added to the dry granules, mixed and compressed to obtain 500 mg of dispersible tablets , The disintegration time of each formulation was measured by the same method as in Example 1 ( see : Table 4). During the preparation of dry granules and formulations, the amount of magnesium stearate ("MgSA") as a lubricant and the amount of microcrystalline cellulose ("mcc") as an excipient were varied as follows in order to prepare Dispersible tablets with 0, 1, 5, 10, 15, 20 or 30% (w/w) lubricant: 0 mg MgSA, 170 mg mcc; 5 mg MgSA, 165 mg mcc; 25 mg MgSA, 145 mg mcc; 50 mg MgSA, 120 mg mcc; 75 mg MgSA , 95mg mcc; 100mg MgSA, 70mg mcc; and 150mg MgSA, 20mg mcc.

Table 4 : Effect of lubricant composition ratio on disintegration time Composition ratio of lubricant (%, w/w) Disintegration time (seconds) 0 1 39 5 40 10 39 15 41 20 40 30 42

As shown in Table 4 above, dry granules could not be properly prepared and disintegration times could not be measured in the absence of added lubricant, and in the case of adding at least 1% (w/w) lubricant, the lubricant The amount had no effect on the disintegration time.

Embodiment 2-4 : determine the optimum composition ratio of excipient

Each dispersible tablet containing the disintegrant, binder and lubricant at various compositional ratios measured in Examples 2-1 to 2-3 was prepared separately.

60 mg of amoxicillin, 15 mg of potassium clavulanate, magnesium stearate ("MgSA-1"), croscarmellose sodium ("ccs-1"), and copovidone ("co-pvp-1") ”) mixing, and then the mixture is fed into a roller press with a roller speed of 5-10 rpm and a screw speed of 5-10 rpm for compression to obtain dry granules. Subsequently, the dry granules were mixed with 5 mg of silicon dioxide, magnesium stearate ("MgSA-2"), croscarmellose sodium ("ccs-2"), copovidone ("co- pvp-2") and microcrystalline cellulose ("mcc") were mixed and compressed, the amounts of these substances are shown in Table 5a below, and the excipient levels were prepared at 0, 10, 20, 30, 40, 50, 60, 70 or 75% (w/w) in 500 mg dispersible tablets.

Table 5a : the content of each component in the dispersible tablet (unit: mg) Composition ratio of excipients (%, w/w) MgSA-1 ccs-1 co-pvp-1 MgSA-2 ccs-2 co-pvp-2 mcc 0 35 74 40 125 111 35 0 10 25 74 40 85 111 35 50 20 15 74 40 45 111 35 100 30 2 74 40 8 111 35 150 40 2 54 40 8 81 35 200 50 2 54 13 8 81 12 250 60 2 34 13 8 51 12 300 70 2 14 13 8 twenty one 12 350 75 2 8 8 8 12 7 375

The disintegration time of each formulation was measured by the same method as in Example 1 ( see : Table 5b).

Table 5b : Effect of composition ratio of excipients on disintegration time Composition ratio of excipients (%, w/w) Disintegration time (seconds) 0 - 10 - 20 - 30 39 40 41 50 40 60 42 70 41 75 40

As shown in Table 5b above, in the case of adding more than 30% of excipients, dispersible tablets can be properly prepared, the addition of excipients can suitably prepare dispersible tablets, and the amount of excipients has nothing to do with the disintegration time.

However, from the viewpoint of the composition ratios measured in Examples 2-1 to 2-3, the composition ratio of the excipient is optimally about 75% (w/w).

Summarizing the results of Examples 2-1 to 2-4, in the dispersible tablet with dry granules as the intermediate, the optimal ratio showing the best disintegration rate and dispersibility is: 6-20% (w/ w) a disintegrant, 0.1-15% (w/w) of a binder, 30-75% (w/w) of an excipient, and no particular limitation on the content of a lubricant.

Embodiment 3 : preparation has the dispersible tablet of various composition ratio

Dry granules containing amoxicillin and clavulanate and binders, disintegrants, lubricants, excipients or mixtures thereof of various compositional ratios determined in Examples 2-1 to 2-4 Dispersible tablets were prepared in order to evaluate disintegration properties.

First, 75 mg (15% (w/w)) of a mixture of amoxicillin and potassium clavulanate (4:1, w/w), magnesium stearate ("MgSA-1"), croscarboxymethyl Sodium cellulose ("ccs-1") and copovidone ("co-pvp-1") were mixed with each other, and the mixture was then fed into a roller press with a roller speed of 5-10 rpm and a screw speed of 5-10 rpm. Compress to obtain dry granules. Subsequently, 5 mg (1% (w/w)) of silicon dioxide, magnesium stearate ("MgSA-2"), croscarmellose sodium ("ccs-2") were added to the dry granules "), copovidone ("co-pvp-2"), and microcrystalline cellulose ("mcc"), mixed, and compressed to prepare 500 mg dispersible tablets. During the preparation of dry granules and formulations, the composition ratio of each component was varied as shown in Table 6a below.

Table 6a : Composition ratio of each component contained in the dispersible tablet (unit: %, w/w) preparation MgSA-1 ccs-1 co-pvp-1 MgSA-2 ccs-2 co-pvp-2 mcc Test example 1 10 3 14 10 3 1 43 Test example 2 15 3 7 15 3 8 33 Test example 3 14 5 1 14 5 14 31 Test example 4 0.5 3 1 0.5 3 1 75 Test example 5 5 8 4 5 8 5 49 Test example 6 0.1 8 5 0.1 8 5 57.8 Test Example 7 1 5 2 0.1 15 2 58.9 Test example 8 0.1 10 1 1 10 1 60.9 Test example 9 0.1 10 0.1 10 10 0.1 53.7

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

Table 6b : Disintegration Time and Particle Size Distribution of Dispersible Tablets preparation Average disintegration time (seconds) d90(μm) d50(μm) d10(μm) control 123 118.4 39.2 9.8 Test example 1 90 86.1 21.0 6.6 Test example 2 89 86.2 21.1 6.5 Test example 3 69 83.7 20.4 6.1 Test example 4 91 82.6 19.9 6.0 Test example 5 55 87.3 20.9 6.4 Test example 6 53 89.7 20.6 6.5 Test example 7 46 83.2 20.3 6.0 Test example 8 44 84.4 20.2 6.1 Test example 9 45 86.1 20.9 6.3

As shown in Table 6b above, it can be clearly determined that the disintegration time of each formulation is different, 30-60% of the control, and the particle size is finer than the control.

Therefore, it can be concluded that the combination of dry granules containing amoxicillin and clavulanate, disintegrants, binders, lubricants and excipients compared with the prior art dispersible tablets The dispersible tablets obtained from the various composition ratios determined in Examples 2-1 to 2-4 showed better disintegration properties.

Embodiment 4 : preparation has the dispersible tablet of various amoxicillin composition ratios

Under the situation of the composition ratio of binding agent, disintegrant, lubricant and excipient of test example 8, change the kind of component, prepare the dispersible tablet containing amoxicillin, show that make in embodiment 3 The formulations disintegrated fastest, and their disintegration properties were measured separately.

First, a mixture of 15% (w/w) amoxicillin and potassium clavulanate (4:1, w/w), 0.1% (w/w) lubricant ("A1"), 10% ( w/w) of the disintegrant ("B1") and 1% (w/w) of the binder ("C1") were mixed and the mixture was then fed into the roller at 5-10 rpm and the screw at 5-10 rpm Compressed in a roller press to obtain dry granules. Subsequently, 1% (w/w) of silicon dioxide, 1% (w/w) of lubricant ("A2"), 10% (w/w) of disintegrant were added to the dry granules ("B2"), 1% (w/w) binder ("C2") and 60.9% (w/w) excipient ("D"), mixed, compressed to prepare 500 mg dispersible tablets . During the preparation of dry granules and formulations, the specific components of disintegrants, lubricants, binders and excipients were varied as shown in Table 7a below.

Table 7a : Details of disintegrants, lubricants, binders and excipients preparation A1 B1 C1 A2 B2 C2 D. Test example 1 MgSA cr-pvp HPC MgSA cr-pvp HPC mcc Test example 2 tc ccs co-pvp tc ccs co-pvp L-HPC Test example 3 SA Na-stg HEC SA Na-stg HEC LA Test example 4 MgSA K-cmc HPMC tc K-cmc HPMC CHP Test example 5 tc pgst co-pvp SA pgst HEC cst Test example 6 SA cr-pvp HPMC MgSA Na-stg HEC Ma Test example 7 MgSA ccs co-pvp SA K-cmc HPMC mcc Test example 8 tc Na-stg HEC MgSA pgst co-pvp L-HPC Test example 9 SA K-cmc HPMC tc cr-pvp HEC LA

^* Abbreviations: Cr-pvp, crospovidone; ccs, croscarmellose sodium; Na-stg, sodium starch glycolate; K-cmc, potassium carboxymethylcellulose; pgst, pregelatinized starch; MgSA, magnesium stearate; tc, talc; PEG, polyethylene glycol; SA, stearic acid; co-pvp, copovidone; pvp, povidone; HPC, hydroxypropylcellulose; HPMC, hydroxypropyl 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 containing amoxicillin made above disintegrates in distilled water in 5ml, analyze respectively average disintegration time and particle size distribution (d90, d50 and d10), wherein contrast is identical with embodiment 1 ( referring to : Table 7b).

Table 7b : Disintegration Time and Particle Size Distribution of Dispersible Tablets preparation Average disintegration time (seconds) d90(μm) d50(μm) d10(μm) control 123 118.4 39.2 9.8 Test example 1 46 86.1 21.0 6.6 Test example 2 45 86.2 21.1 6.5 Test example 3 45 83.7 20.4 6.1 Test example 4 46 82.6 19.9 6.0 Test example 5 44 87.3 20.9 6.4 Test example 6 45 89.7 20.6 6.5 Test example 7 46 83.2 20.3 6.0 Test example 8 45 84.4 20.2 6.1 Test example 9 44 86.1 20.9 6.3

As shown in Table 7b above, the disintegration time did not appear to be different in each formulation, indicating that the disintegration did not vary with the type of disintegrant, lubricant, binder and excipient.

Example 5 : Preparation of Dispersible Tablets by Various Methods

Based on the results of Examples 3 and 5, it is shown that the dispersible tablets containing amoxicillin, binding agent, disintegrant, lubricant and excipient whose composition is determined in Example 2 show the same disintegration performance, and the composition The change of the composition has no effect on the disintegration performance, check whether the binder, disintegrant, lubricant and excipient have the same composition and composition ratio and the dispersible tablets containing amoxicillin prepared by various methods show Similar disintegration properties.

Example 5-1 : Preparation of Amoxicillin-containing Dispersible Tablets by Using Two Types of Dry Granules

First, a mixture of 15% (w/w) amoxicillin and potassium clavulanate (4:1, w/w), 0.1% (w/w) magnesium stearate, 10% (w/w ) of croscarmellose sodium and 1% (w/w) of copovidone are mixed with each other, and then the mixture is sent to a roller press with a roller speed of 5-10 rpm and a screw speed of 5-10 rpm for compression , to obtain dry particles.

Subsequently, 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose were added to the dry granules The copovidone of plain sodium, 1% (w/w) and the microcrystalline cellulose of 60.9% (w/w) are mixed with each other, and then the mixture is sent into a roller speed of 5-10rpm and a screw speed of 5-10rpm. Compression in a roller compactor to prepare another dry granulate.

Said two kinds of dry granules were mixed with each other and compressed to prepare 500 mg dispersible tablets ("Test Example 1").

At the same time, in order to prepare dispersible tablets as a control, a mixture of 15% (w/w) of amoxicillin and potassium clavulanate (4:1, w/w), 0.1% (w/w) of stearin Magnesium nitrate, croscarmellose sodium of 10% (w/w) and copovidone of 1% (w/w) are mixed with each other, then the mixture is sent to the roller speed of 5-10rpm and the screw speed of 5 Compression was performed in a roller press at -10 rpm to obtain dry granules. Subsequently, 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose were added to the dry granules Sulfate sodium, 1% (w/w) copovidone and 60.9% (w/w) microcrystalline cellulose were mixed and compressed to prepare 500 mg dispersible tablets.

Example 5-2 : Preparation of amoxicillin-containing dispersible tablets using dry granules and wet granules

First, a mixture of 15% (w/w) amoxicillin and potassium clavulanate (4:1, w/w), 0.1% (w/w) magnesium stearate, 10% (w/w ) of croscarmellose sodium and 1% (w/w) of copovidone are mixed with each other, and then the mixture is sent to a roller press with a roller speed of 5-10 rpm and a screw speed of 5-10 rpm for compression , to obtain dry particles.

Subsequently, 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose were added to the dry granules sodium bismuth, 1% (w/w) copovidone and 60.9% (w/w) microcrystalline cellulose, mixed with each other, then some distilled water and 1% (w/w) copovidone were added to the mixture , and then subject the mixture to a series of blending, granulation, drying and standardization treatments to obtain wet granules.

The dry granules and wet granules thus obtained by the above method were mixed with each other and compressed to prepare 500 mg dispersible tablets ("Test Example 2") in which the control was the same as in Example 5-1.

Example 5-3 : Preparation of Dispersible Tablets Containing Amoxicillin Using Wet Granules and Dry Granules

First, 12% (w/w) amoxicillin, 0.1% (w/w) magnesium stearate, 10% (w/w) croscarmellose sodium and 1% (w/w) The copovidones of w) were mixed with each other, some distilled water and 1% (w/w) copovidone were added to the mixture, and then said mixture was blended, granulated, dried and standardized to obtain wet granules.

Subsequently, 3% (w/w) of potassium clavulanate, 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 each other, and then the mixture was fed into rollers Compression is carried out in a roller press with a speed of 5-10 rpm and a screw speed of 5-10 rpm to obtain dry granules.

The wet granules and dry granules thus obtained were mixed with each other and compressed to prepare a 500 mg dispersible tablet ("Test Example 3") in which the control was the same as in Example 5-1.

Example 5-4 : Preparation of Dispersible Tablets Containing Amoxicillin by Using Two Types of Wet Granules

First, 12% (w/w) amoxicillin, 0.1% (w/w) magnesium stearate, 10% (w/w) croscarmellose sodium and 1% (w/w) The copovidones of w) are mixed with each other, and then the mixture is blended, granulated, dried and standardized to obtain wet granules.

Subsequently, 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose were added to the dry granules Plain sodium and 60.9% (w/w) microcrystalline cellulose were mixed with each other, some distilled water and 1% (w/w) copovidone were added to the mixture, and wet granules were obtained similarly to the above.

The two wet granules thus obtained were mixed with 3% (w/w) potassium clavulanate and compressed to prepare 500 mg dispersible tablets ("Test Example 4"), wherein the control was the same as in Example 5-1.

Embodiment 5-5 : the comparison of dispersion performance

Each dispersible tablet in the test examples 1-4 prepared by the control and Examples 5-1 to 5-4 was disintegrated in 5 ml of distilled water, and the average disintegration time and Particle size distribution (d90, d50 and d10) ( see : Table 8).

Table 8 : Disintegration Time and Particle Size Distribution of Dispersible Tablets preparation Average disintegration time (seconds) d90(μm) d50(μm) d10(μm) control 46 83.2 20.3 6.0 Test example 1 46 86.1 21.0 6.6 Test example 2 45 86.2 21.1 6.5 Test example 3 120 103.7 37.4 9.1 Test example 4 125 105.6 40.9 9.5

As shown in Table 8 above, the dispersible tablets prepared with dry granules containing amoxicillin and potassium clavulanate (i.e., Test Examples 1 and 2) exhibited the same disintegration performance as the control, while those prepared with dry granules containing amoxicillin Those made with wet granules of cillin (i.e., Test Examples 3 and 4) had significantly increased disintegration times as well as reduced dispersibility, indicating that they had similar disintegration properties to the formulations described in PCT International Publication WO 04/06917 .

Therefore, it can be concluded that in order to prepare the dispersible tablet of the present invention exhibiting excellent disintegration properties, dry granules containing amoxicillin and potassium clavulanate should be used, while the subsequent process can be different.

Embodiment 6 : preparation contains the dispersible tablet of amoxicillin and foaming agent

Based on the knowledge that foaming agents affect disintegration time and dispersibility together with disintegrants and binders, the disintegration performance of the dispersible tablet of the present invention by foaming agents was examined.

Embodiment 6-1 : preparation contains the dispersible tablet of amoxicillin and foaming agent

First, a mixture of 15% (w/w) amoxicillin and potassium clavulanate (4:1, w/w), 0.1% (w/w) magnesium stearate, 10% (w/w ) of croscarmellose sodium, 2% (w/w) of citric acid, 2% (w/w) of sodium bicarbonate and 1% (w/w) of copovidone were mixed with each other, and then The mixture is fed into a roller press with a roller speed of 5-10 rpm and a screw speed of 5-10 rpm for compression to obtain dry granules. Subsequently, 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose were added to the dry granules sodium bicarbonate, 1% (w/w) copovidone, 2% (w/w) citric acid, 2% (w/w) sodium bicarbonate and 72.9% (w/w) microcrystalline cellulose , mixed with each other, and compressed to prepare 500 mg dispersible tablets ("test example").

Meanwhile, as a control, a mixture of 15% (w/w) of amoxicillin and potassium clavulanate (4:1, w/w), 0.1% (w/w) of magnesium stearate, 10% ( w/w) of croscarmellose sodium and 1% (w/w) of copovidone are mixed with each other, and then the mixture is fed into a roll press with a roll speed of 5-10 rpm and a screw speed of 5-10 rpm compressed to obtain dry granules. Subsequently, 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose were added to the dry granules Sulfate sodium, 1% (w/w) copovidone and 60.9% (w/w) microcrystalline cellulose were mixed and compressed to prepare 500 mg dispersible tablets.

Each dispersible tablet in the control and the test example was disintegrated in 5ml distilled water, and the average disintegration time and particle size distribution (d90, d50 and d10) were analyzed respectively by the method described in Example 1 ( see : Table 9a).

Table 9a : Disintegration Time and Particle Size Distribution of Dispersible Tablets preparation Average disintegration time (seconds) d90(μm) d50(μm) d10(μm) control 46 83.2 20.3 6.0 Test case 30 86.1 21.0 6.6

As shown in Table 9a above, although the dispersible tablet containing foaming agent (ie, Test Example) showed a significant decrease in disintegration time when compared to the control, there was no difference in dispersibility.

Embodiment 6-2 : determine the optimal composition ratio of blowing agent

Based on the results of Example 6-1 showing that the foaming agent facilitated the disintegration of the dispersible tablet, the composition ratio of the foaming agent for obtaining the best disintegration performance was determined by the following test.

First, a mixture of 15% (w/w) amoxicillin and potassium clavulanate (4:1, w/w), 0.1% (w/w) magnesium stearate, 10% (w/w ), foaming agent (1:1 (w/w) mixture of citric acid powder and sodium bicarbonate) and 1% (w/w) copovidone were mixed with each other, and then The mixture is fed into a roller press with a roller speed of 5-10 rpm and a screw speed of 5-10 rpm for compression to obtain dry granules. Subsequently, 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose were added to the dry granules Sulfate sodium, 1% (w/w) copovidone, foaming agent and microcrystalline cellulose were mixed with each other and compressed to prepare 500 mg dispersible tablets. In the process of preparing dry granules and formulations, the amount of foaming agent ("SHC") and the amount of microcrystalline cellulose ("mcc") as excipients were varied as follows so that the preparation contains 0-15% ( w/w) Dispersed tablet of effervescent agent, and the disintegration time was measured by the method described in Example 1 ( see : Table 9b): 60.9% (w/w) mcc; 1% (w/w) SHC, 59.9 %(w/w)mcc; 2%(w/w)SHC, 58.9%(w/w)mcc; 3%(w/w)SHC, 57.9%(w/w)mcc; 4%(w/w) ) SHC, 56.9% (w/w) mcc; 5% (w/w) SHC, 55.9% (w/w) mcc; 6% (w/w) SHC, 54.9% (w/w) mcc; 7% (w/w) SHC, 53.9% (w/w) mcc; 8% (w/w) SHC, 52.9% (w/w) mcc; 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 : Effect of composition ratio of blowing agent on disintegration time Composition ratio of blowing agent (%, w/w) Disintegration time (seconds) 0 48 1 47 2 40 3 39 4 38 5 36 6 34 7 32 8 30 9 29 10 28 11 28 12 28 13 28 14 28 15 28

As shown in Table 9b above, the dispersible tablet containing effervescent agent disintegrated faster than the formulation without effervescent agent. In particular, the addition of more than 2% (w/w) foaming agent, the disintegration time decreased rapidly, and the addition of more than 10% (w/w) foaming agent found that the disintegration time no longer decreased.

Embodiment 6-3 : prepare the dispersible tablet containing amoxicillin that each composition ratio is different

Within the range of each composition ratio determined in Example 6-2, amoxicillin-containing dispersible tablets were prepared while varying the foaming agent composition ratio, and the disintegration properties of each preparation were examined separately.

First, a mixture of 15% (w/w) amoxicillin and potassium clavulanate (4:1, w/w), 0.1% (w/w) magnesium stearate, 10% (w/w ), foaming agent (1:1 (w/w) mixture of citric acid powder and sodium bicarbonate) (“A1”), and 1% (w/w) copovidone mixed with each other, and then the mixture is sent to a roller press with a roller speed of 5-10 rpm and a screw speed of 5-10 rpm for compression to obtain dry granules. Subsequently, 1% (w/w) of silicon dioxide, 1% (w/w) of magnesium stearate, 10% (w/w) of croscarmellose were added to the dry granules Sulfate sodium, 1% (w/w) copovidone, foaming agent ("A2") and microcrystalline cellulose ("B") were mixed and compressed to prepare 500 mg dispersible tablets. The compositional ratios of the blowing agents (A1, A2) and microcrystalline cellulose (B) are shown in Table 9c below.

Table 9c : composition ratio of blowing agent and microcrystalline cellulose (unit: %, w/w) preparation A1 ^* A2 ^* B Test example 1 0 0 60.9 Test example 2 0 10 50.9 Test example 3 10 0 50.9 Test example 4 5 4 51.9 Test example 5 2 1 57.9 Test example 6 0 5 59.9 Test example 7 3 7 50.9 Test example 8 7 2 51.9 Test example 9 5 0 55.9

^* The compositions of A1 and A2 are the same as each other.

Each dispersible tablet containing amoxicillin was disintegrated in 5ml of distilled water, and the average disintegration time and particle size distribution (d90, d50 and d10) were analyzed respectively, wherein the control was the same as in Example 1 ( see : Table 9d ).

Table 9d : Disintegration Time and Particle Size Distribution of Dispersible Tablets preparation Average disintegration time (seconds) d90(μm) d50(μm) d10(μm) Test example 1 48 86.1 21.0 6.6 Test example 2 28 86.2 21.1 6.5 Test example 3 27 83.7 20.4 6.1 Test example 4 29 82.6 19.9 6.0 Test example 5 39 87.3 20.9 6.4 Test example 6 36 89.7 20.6 6.5 Test Example 7 28 83.2 20.3 6.0 Test example 8 29 84.4 20.2 6.1 Test example 9 36 86.1 20.9 6.3

As shown in Table 9d above, the disintegration time does not depend on the time of adding the blowing agent, but the disintegration time changes with the composition ratio of the blowing agent.

Example 7 : Preparation of dispersible tablets containing various β-lactam antibiotics and evaluation of disintegration properties

Separately, dispersible tablets containing β-lactam antibiotics such as penicillin or picillin instead of amoxicillin were prepared and the disintegration time and particle size distribution (d90, d50 and d10) of the formulations were analyzed.

Example 7-1 : Preparation of Penicillin-containing Dispersible Tablets and Evaluation of Disintegration Properties

Mix 188 mg of a mixture of penicillin and potassium clavulanate (2:1, w/w), 30 mg of crospovidone, 8 mg of copovidone, 23 mg of silicon dioxide, 8 mg of magnesium stearate, 9 mg of citric acid and 11 mg of sodium bicarbonate mixed with each other, and then the mixture is sent to a roller press with a roller speed of 5-10 rpm and a screw speed of 5-10 rpm for compression to obtain dry granules. Subsequently, 15 mg of low-substituted hydroxypropyl cellulose, 145 mg of microcrystalline cellulose, 47 mg of crospovidone, 9 mg of magnesium stearate and 7 mg of povidone were added to the dry granules, mixed and compressed to prepare a 500 mg dispersion tablet. The disintegration time and particle size distribution (d90, d50 and d10) of the formulations were analyzed respectively ( see : Table 10a).

Table 10a : Disintegration time and particle size distribution of penicillin-containing dispersible tablets Average disintegration time (seconds) 35 d90(μm) 102.4 d50(μm) 38.2 d10(μm) 8.7

Example 7-2 : Preparation of dispersible tablets containing pampicillin and evaluation of disintegration properties

Mix 156mg of a mixture of paminocillin and potassium clavulanate (4:1, w/w), 48mg of crospovidone, 9mg of copovidone, 25mg of silicon dioxide, 7mg of magnesium stearate, 9mg of citric acid and 11mg of carbonic acid Sodium hydrogen is mixed with each other, and then the mixture is sent to a roller press with a roller speed of 5-10 rpm and a screw speed of 5-10 rpm for compression to obtain dry granules. Subsequently, 113 mg microcrystalline cellulose, 60 mg lactic acid, 42 mg crospovidone, 12 mg magnesium stearate and 8 mg povidone were added to the dry granules, mixed and compressed to prepare 500 mg dispersible tablets. The disintegration time and particle size distribution (d90, d50 and d10) of the formulations were analyzed respectively ( see : Table 10b).

Table 10b : Disintegration time and particle size distribution of dispersible tablets containing pampicillin Average disintegration time (seconds) 38 d90(μm) 92.4 d50(μm) 35.1 d10(μm) 8.1

As shown in the results of Examples 7-1 and 7-2, it can be clearly determined that, in addition to amoxicillin, the method for preparing the dispersible tablet of the present invention can also contain various β-lactam antibiotics such as penicillin or pamicillin , the preparation prepared by this method can reduce the average disintegration time and exhibit excellent dispersion performance, which indicates that the method of the present invention can be practically used in the preparation of various β-lactam antibiotics.

use

The dispersible tablet containing β-lactam antibiotic of the present invention can be administered with the dosage of 5-20mg/body weight (kg) with the concentration of 20-50mg/mL (dispersed in water), dosage varies with patient's age, sex, symptom , mode of administration or purpose of prophylaxis. For patients showing specific symptoms, those skilled in the art can change the individual dosage according to the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, disease severity, etc.

As clearly explained and shown above, the present invention provides dispersible tablets containing β-lactam antibiotics, wherein the β-lactam antibiotics and clavulanate are formulated in tablet form, which are easy to take when disintegrating in water, the present invention The invention also provides a method for preparing the dispersible tablet. The dispersible tablet of the present invention can be practically used for treating diseases requiring β-lactam antibiotics because it can be easily taken by infants or elderly patients who have difficulty in oral administration and has improved disintegration rate and dispersibility.

It will be appreciated that the above description is a description of the preferred embodiments only and is not intended to limit the invention to the particular forms set forth, but that the invention, in contrast, includes such changes and variations within the spirit and scope defined in the claims. and equivalents.

Claims (32)

1. The method for preparing the dispersible tablet containing β-lactam antibiotic, comprises steps: (i) mixing β-lactam antibiotics and clavulanate with disintegrants, lubricants and binders, and then sending the mixture into a roller compactor to obtain dry granules; then, (ii) mixing the dry granules obtained in step (i) with excipients, disintegrants, lubricants and binders, and compressing the mixture to obtain dispersible tablets. 2. The method for producing a dispersible tablet containing a β-lactam antibiotic according to claim 1, wherein the β-lactam antibiotic is a penicillin antibiotic. 3. The method for preparing dispersible tablets containing β-lactam antibiotics according to claim 2, wherein the penicillin antibiotics are penicillin, amoxicillin, ampicillin, cyclohexicillin, epixicillin, phenicillin or pampicillin. 4. The process for the preparation of dispersible tablets containing [beta]-lactam antibiotics according to claim 1, wherein the clavulanate is potassium clavulanate. 5. the method for preparing the dispersible tablet containing β-lactam antibiotic of claim 1, wherein the mixture of β-lactam antibiotic and clavulanate in step (i) is with 15-40% (w/w) Composition ratios are included in dispersible tablets. 6. the method for preparing the dispersible tablet containing β-lactam antibiotic of claim 1, wherein the disintegrating agent in the step (i) is crospovidone, croscarmellose sodium, sodium starch glycolate, Potassium carboxymethylcellulose, pregelatinized starch or a mixture thereof, and included in the dispersible tablet at a composition ratio of 3-10% (w/w). 7. the method for preparing the dispersible tablet containing β-lactam antibiotic of claim 1, wherein the lubricant in step (i) is magnesium stearate, silicon dioxide, talcum, polyethylene glycol, stearic acid or A mixture thereof, and included in a dispersible tablet at a composition ratio of 0.1-5% (w/w). 8. The method for preparing dispersible tablets containing β-lactam antibiotics according to claim 1, wherein the binding agent in step (i) is copovidone, povidone, hydroxypropyl cellulose, hydroxypropyl methyl Cellulose, hydroxyethylcellulose or a mixture thereof, and included in the dispersible tablet at a composition ratio of 0.1-7.5% (w/w). 9. the method for preparing the dispersible tablet containing β-lactam antibiotic of claim 1, wherein in the process of step (i), desiccant or whipping agent are further added to β-lactam antibiotic and clavulanate, In a mixture of disintegrants, lubricants and binders. 10. the method for preparing the dispersible tablet containing β-lactam antibiotic of claim 9, wherein desiccant is silicon dioxide, synthetic aluminum silicate, light anhydrous silicic acid or its mixture, and with 0.1-10% ( The composition ratio of w/w) is included in the dispersible tablet. 11. the method for preparing the dispersible tablet containing β-lactam antibiotic of claim 9, wherein foaming agent is citric acid, tartaric acid, alginic acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or A mixture thereof, and included in a dispersible tablet at a composition ratio of 1-5% (w/w). 12. The method for preparing dispersible tablets containing β-lactam antibiotics according to claim 1, wherein the excipient in 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 at a composition ratio of 30-75% (w/w). 13. the method for preparing the dispersible tablet containing β-lactam antibiotic of claim 1, wherein the disintegrating agent in the step (ii) is crospovidone, croscarmellose sodium, sodium starch glycolate, Potassium carboxymethylcellulose, pregelatinized starch or a mixture thereof, and included in the dispersible tablet at a composition ratio of 3-10% (w/w). 14. The method for preparing dispersible tablets containing β-lactam antibiotics according to claim 1, wherein the lubricant in step (ii) is magnesium stearate, silicon dioxide, talcum, polyethylene glycol, stearic acid or A mixture thereof, and included in a dispersible tablet at a composition ratio of 0.1-5% (w/w). 15. The method for preparing the dispersible tablet containing β-lactam antibiotic of claim 1, wherein the binding agent in step (ii) is copovidone, povidone, hydroxypropyl cellulose, hydroxypropyl methyl Cellulose, hydroxyethylcellulose or a mixture thereof, and included in the dispersible tablet at a composition ratio of 0.1-7.5% (w/w). 16. the method for preparing the dispersible tablet containing β-lactam antibiotic of claim 1, wherein the excipient in step (ii), disintegrant, lubricant and binding agent are in powder form and in step (i) The obtained dry granules are blended. 17. the method for preparing the dispersible tablet containing β-lactam antibiotic of claim 1, wherein the excipient in step (ii), disintegrating agent, lubricant and binding agent are obtained by mixing and compressing these materials The dry granulate form is mixed with the dry granulate obtained in step (i). 18. the method for preparing the dispersible tablet containing β-lactam antibiotic of claim 1, wherein the excipient in step (ii), disintegrant, lubricant and binding agent are obtained by mixing these materials with water The wet granulated form of is mixed with the dry granulated obtained in step (i). 19. The method for preparing the dispersible tablet containing β-lactam antibiotic according to claim 1, wherein in the process of step (ii), foaming agent is further added to the dry granules and excipients obtained in step (i) , disintegrants, lubricants and binders in a mixture. 20. The method for preparing dispersible tablets containing β-lactam antibiotics according to claim 19, wherein the foaming agent is citric acid, tartaric acid, alginic acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or A mixture thereof, and included in a dispersible tablet at a composition ratio of 1-5% (w/w). 21. Dispersible tablets containing β-lactam antibiotics prepared according to claim 1, comprising 15-40% (w/w) of a mixture of β-lactam antibiotics and clavulanate as active in terms of dispersible tablets components, and 6-20% (w/w) of disintegrants, 0.1-10% (w/w) of lubricants, 0.1-15% (w/w) of binders, 30-75% ( w/w) excipients. 22. The dispersible tablet containing a [beta]-lactam antibiotic according to claim 21, wherein the [beta]-lactam antibiotic is a penicillin antibiotic. 23. The dispersible tablet containing a [beta]-lactam antibiotic according to claim 22, wherein the penicillin antibiotic is penicillin, amoxicillin, ampicillin, cyclohexicillin, epicillin, phenicillin or pampicillin. 24. The dispersible tablet containing a [beta]-lactam antibiotic according to claim 21, wherein the clavulanate is potassium clavulanate. 25. The dispersible tablet containing β-lactam antibiotic according to claim 21, wherein the disintegrant is crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose potassium, pregelatin starches or mixtures thereof. 26. The dispersible tablet containing a [beta]-lactam antibiotic according to claim 21, wherein the lubricant is magnesium stearate, silicon dioxide, talc, polyethylene glycol, stearic acid or a mixture thereof. 27. The dispersible tablet containing β-lactam antibiotic according to claim 21, wherein the binding agent is copovidone, povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose or its mixture. 28. The dispersible tablet containing β-lactam antibiotic according to claim 21, wherein the excipient is microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, calcium hydrogen phosphate, corn starch, mannitol, sorbose alcohol, xylitol or mixtures thereof. 29. The dispersible tablet containing a β-lactam antibiotic according to claim 21, wherein a foaming agent, a desiccant or a mixture thereof is further included in the dispersible tablet. 30. The dispersible tablet containing β-lactam antibiotics according to claim 29, wherein the foaming agent is citric acid, tartaric acid, alginic acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or a mixture thereof, And included in the dispersible tablet at a composition ratio of 2-10% (w/w). 31. The dispersible tablet containing β-lactam antibiotics according to claim 29, wherein the desiccant is silicon dioxide, synthetic aluminum silicate, light anhydrous silicic acid or a mixture thereof, and is added at 0.1-10% (w/w ) composition ratio is included in the dispersible tablet. 32. Amoxicillin-containing dispersible tablets comprising 15-40% (w/w) of a mixture of amoxicillin and clavulanate (4:1, w/w) on a dispersible tablet basis, and 6 -20% (w/w) disintegrant, 0.1-10% (w/w) lubricant, 0.1-15% (w/w) binder, 30-75% (w/w) Excipients, 2-10% (w/w) foaming agent and 0.1-10% (w/w) desiccant.