WO2007058397A1

WO2007058397A1 - A dispersible tablet comprising the mixture of amoxicillin and clavulanic acid or its salts and processes for preparing the same

Info

Publication number: WO2007058397A1
Application number: PCT/KR2005/003891
Authority: WO
Inventors: Woo Heon Song; Jun Sang Park; Hun Sik Wang
Original assignee: GL Pharmtech Corp
Current assignee: GL Pharmtech Corp
Priority date: 2005-11-17
Filing date: 2005-11-17
Publication date: 2007-05-24
Anticipated expiration: 2008-05-17

Abstract

This invention relates to an oral dispersible tablet comprising amoxicillin and clavulanic acid or its salts and process thereof, characterized by the following two steps of: (A) preparing a dry granulate by roller compaction process, in which the intragranular ingredients include a mixture of amoxicillin and clavulanic acid or its salts as active ingredients, a disintegrant and a lubricant in the amount of 0.5-1.5 weight% based on the total granulate weight and microcrystalline cellulose in the amount of 5-15 weight% based on the total granulate weight, and (B) tabletting the dry granulate, so obtained from (A) step, with the extragranular ingredients including a disintegrant, a lubricant and microcrystalline cellulose in the amount of 20-40 weight% based on the total tablet weight.

Description

A DISPERSIBLE TABLET COMPRISING THE MIXTURE OF

AMOXICILLIN AND CLA VULANIC ACID OR ITS SALTS AND

PROCESSES FOR PREPARING THE SAME

Technical Field

[1] This invention relates to an oral dispersible tablet using formulations comprising amoxicillin and clavulanic acid or its salts, and processes for preparing the same.

[2]

Background Art

[3] Amoxicillin is a typical beta-lactam antibiotic with a broad spectrum of antibacterial activity. Clavulanic acid is a beta- lactamase inhibitor to counter a beta- lactamase mediated resistance mechanism. The combination of amoxicillin and clavulanic acid is an effective treatment for bacterial infections and may be administered by oral dosage forms, for instance, film-coated tablets and a dry syrup for especially pediatric patients.

[4]

[5] Among the commercially available formulations of amoxicillin and clavulanic acid, a dry syrup is dispensed in a certain amount of water for reconstitution into suspensions, which are useful for children or elderly patients who have serious problems with swallowing such a solid dosage forms, especially the larger one.

[6]

[7] However, due to the fact that clavulanic acid is extremely sensitive to moisture, such suspensions have serious drawbacks: They have to be prepared by the pharmacist shortly before delivery to the patient. The suspension should be kept cool in a refrigerator because otherwise it is liable to loss of contents and discoloration. When administered its one-time dose has to be measured with a spoon or cup with inherent inaccuracy of the dosage volume for pediatric patients.

[8]

[9] A dispersible tablet may overcome these drawbacks. The dispersible tablet is designed to be disintegrated and dispersed rapidly when immersed in a small amount of water for reconstitution into such suspensions. As one tablet contains one-time dose of active ingredients, patients are allowed to take an accurate amount of drug and are also easy to swallow due to easier dispersion in water. Further, the use of dispersible tablet is quite useful to prevent reduced contents of clavulanic acid and its discoloration during long-term storage, as one-time dosage is dispersed in a small of water prior to administration. [10]

[11] According to the regulations of the European Pharmacopoeia (The fifth revised edition), dispersible tablets should be disintegrated within 3 minutes when immersed in water of 15-25⁰C, and dispersed particle sizes should be in the range of less than 710 D.

[12]

[13] To improve appropriate physico-chemical properties of an oral dispersible tablet containing amoxicillin and clavulanic acid, a variety of approaches have been exercised.

[14]

[15] The Korean Patent Publication No. 1996-9182 describes an amphoteric beta-lactam antibiotic as a dispersible tablet which has been prepared by wet granulation process, using an amorphous or fine cellulose as an intragranular disintegrant and low- substituted hydroxypropyl cellulose as an extragranular disintegrant.

[16]

[17] However, the dispersible tablet containing amoxicillin and clavulanic acid has been seriously restricted during the process of wet granulation, while excipients contained in the dispersible tablet places serious restrictions on its formulation due to their hygro- scopicity and moisture content.

[18]

[19] The conventional method for manufacturing the dispersible tablet has focused on wet granulation process, but this has led to chemical discomposition of clavulanic acid during the process because clavulanic acid is extremely sentitive to moisture.

[20]

[21] Furthermore, in order to prepare granulate for dispersible tablet via dry granulation process instead of wet granulation process, hydrophobic lubricants should be essentially contained in the granulate but these excipients appear to slow down the disintegration of granulate and/or tablet.

[22]

[23] One way to prepare the dispersible tablet containing amoxicillin and clavulanic acid has been suggested tabletting granulate which is prepared via dry granulation process.

[24]

[25] The conventional dry granulation method is performed through roller compaction.

Diluents or binders should be necessary to compact the powder mixture for granulate and a certain amount of hydrophobic lubricants should be contain to prevent adherence of the granulated powder to metal machinery parts in a roller compactor.

[26]

[27] However, the disintegration time of the dispersible tablet may significantly vary depending on the types and amounts of diluents, binders and lubricants. [28]

[29] The Korean Patent No. 228450 discloses a dispersible tablet formulation containing a beta-lactam antibiotic and clavulanic acid or its salts. The tablet formulation comprise granulate which is prepared by roller compaction and contain intragranular disintegrants such as N-vinyl-2-pyrrolidone, corn starch, rice starch, croscarmellose sodium, formaldehyde casein or mixture thereof.

[30]

[31] However, the conventional process restricts the amount of a lubricant by less than

0.5 weight% to the total tablet weight and as a result, serious adherence of the granulated powder to metal machinery parts (e.g. a roller compactor) may occur during the dry granulation process and tabletting process.

[32] In comparison, if the amount of a lubricant exceeds 0.5 weight% of the total tablet, a hydrophobic film is formed at the surface of the tablet that will slow down the disintegration time.

[33]

[34] To overcome the aforementioned adherence of the granulated powder to metal machinery parts in the dry granulation process for dispersible tablets containing amoxicillin and clavulanic acid or its salts thereof, the inventors of this invention have conducted extensive experimentation.

[35] Surprisingly, the inventors of this invention discovered that the use of widely used microcrystalline cellulose as a diluent in a specific ratio may easily prepare dispersible tablets in the absence of such adherence and that the tablet is rapidly disintegrated within 1 minute, when immersed in water. Thus we consummated this invention.

[36]

Disclosure of Invention Technical Problem

[37] The object of this invention is to provide an oral dispersible tablet using formulations comprising amoxicillin and clavulanic acid or its salts and its manufacturing method that may solve the adherence of the granulated ingredients to metal machinery parts during the dry granulation process.

[38]

[39] Another object of this invention is to provide an oral dispersible tablet using formulations comprising amoxicillin and clavulanic acid or its salts, wherein the dispersible tablet prepared by the dry granulation process using roller compaction is rapidly disintegrated, when immersed in water.

[40]

Technical Solution [41] This invention is to provide an oral dispersible tablet using formulations comprising amoxicillin and clavulanic acid or its salts thereof with intragranular and extragranular ingredients whose preparation is available by a dry granulation process using roller compaction and tabletting, characterized in that:

[42]

[43] - such intragranular ingredients include a lubricant and a microcrystalline cellulose in the amounts of 0.5-1.5 weight% and 5-15 weight%, respectively, based on the total granulate weight, and

[44] - such extragranular ingredients include 20-40 weight% of microcrystalline cellulose based on the total tablet weight.

[45]

[46] The oral dispersible tablet using formulations comprising amoxicillin and clavulanic acid or its salts in a weight ratio of 12:1 to 1:1 and the active ingredients per tablet comprise 62.5/15.625mg, 125/31.25mg, 125/62.5mg, 200/50mg and 250/125mg of amoxicillin and clavulanic acid; the active ingredients are present by the volume of 50-70 weight% based on the total granulate weight.

[47]

[48] The preparation of dispersible tablet of this invention containing amoxicillin and clavulanic acid comprise following two steps; a dry granulation and tabletting.

[49] Further, the granulate of this invention is produced by roller compaction.

[50]

[51] Surprisingly, the dispersible tablet of this invention using microcrystalline cellulose as a diluent does not slow down the disintegration, unlike other pharmaceutical acceptable diluents such as D-mannitol or lactose.

[52] However, the physical properties of dry granulate and disintegration of the dispersible tablet may significantly vary depending on the Intragranular and extragranular ratio of microcrystalline cellulose.

[53] Surprisingly, according to this invention, the use of the intragranular micro- crystalline cellulose in the amount of more than 5 weight% based on the total granulate weight may lead to favorable compaction of granulated powder during the dry granulation process without adherence of the granulated powder to metal machinery parts in a roller compactor.

[54]

[55] Further, according to this invention, the use of the intragranular microcrystalline cellulose in the amount of less than 15 weight% based on the total weight of the granulate and of the extragranular microcrystalline cellulose in the amount of more than 20 weight% based on the total tablet weight may lead to obtainment of a suitable dispersible tablet, thus ensuring the optimal disintegration and proper hardness to prevent the physical damage of tablet during storage. In addition, the dispersible tablet of this invention may minimize the amount of the extragranular disintegrant which accelerate the discomposition of clavulanic acid due to its severe hygroscopicity.

[56]

[57] The intragranular disintegrant of this invention is selected from a group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, polacrilin potassium and mixture thereof; such disintegrant is present in the amount of 2-5 weight% based on the total granulate weight.

[58]

[59] The intragranular lubricant of this invention is selected from a group consisting of stearic acid or its salts, talc, colloidal silicon dioxide, magnesium silicate, glyceryl behenate, sodium stearyl fumarate and mixture thereof; such lubricant is present in the amount of 0.5-2 weight% based on the total granulate weight.

[60]

[61] The granular composition may also include a pharmaceutically acceptable, a moisture scavenger (e.g. silicon dioxide), a sweetener (e.g. acesulfam potassium) and a pigment (e.g. iron oxide).

[62]

[63] The particle size of the granulate of this invention is preferably in the range of 75D to

1.4mm. The granulate has a particle size of 710D or less, when immersed in water and is present in the amount of 60-80 weight% base on the total tablet weight.

[64]

[65] According to this invention, an oral dispersible tablet is prepared using the granulate, a microcrystalline cellulose as a extragranular dilent in the amount of 20-40 weight% based on the total tablet weight, a disintegrant and a lubricant.

[66] The amount of extragranular microcrystalline cellulose should not exceed 40 weight% based on the total table weight, since the total granulate weight is in the amount of 60-80 weight% based on the total tablet weight.

[67]

[68] The appropriate extragranular disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, sodium lauryl sulfate and mixture thereof; such disintegrant is present in the amount 3-10 weight% based on the total tablet weight.

[69]

[70] The appropriate extragranular lubricant is selected from the group consisting of stearic acid or its salts, talc, colloidal silicon dioxide, magnesium silicate, glyceryl behenate, sodium stearyl fumarate, poloxamer and mixture thereof; such lubricant is present in the amount of 0.5-1.5 weight% based on the total tablet weight. [71]

[72] The oral dispersible tablet of this invention may encompass a pharmaceutically acceptable flavor and pigment.

[73] The oral dispersible tablet of this invention has hardness of more than 3 kp with friability of less than 0.5%. The dispersible tablet of this invention is completely disintegrated within 1 minute, when immersed in water of 15-25⁰C and easily dispersed to form suspensions.

[74]

[75] Another embodiment of this invention is to provide a method for preparing an oral dispersible tablet comprising the following steps of:

[76] (A) preparing a dry granulate, via roller compaction, containing amoxicillin and clavulanic acid or its salts with an intragranular disintegrant and a lubricant in the amount of 0.5-1.5 weight% based on the total granulate weight plus microcrystalline cellulose in the amount of 5-15 weight% based on the total granulate weight as a diluent, and

[77] (B) tabletting the dry granulate, so obtained from (A) step, with another micro- crystalline cellulose in the amount of 20-40 weight% based on the total tablet weight.

[78]

[79] The dry granulation process is conducted by roller compaction (e.g. roller compactor, Freund Co.). The granulated powder is compressed to mold sheets under the following conditions: roller speed (2-10 rpm), screw speed (5-20 rpm) and pressure (5-10 MPa). The sheets are passed through #14 to #20 sieves to obtain an appropriate size of granulate.

[80] The granulate, so obtained, is further mixed with a disintegrant, a lubricant and microcrystalline cellulose in the amount of more than 20 weight% based on the total tablet weight and tabletted using a tabletting machine (e.g. rotary tableting machine, ERWEKA Co.) that is widely used in the pharmaceutical industry.

[81]

Advantageous Effects

[82] The oral dispersible tablet of this invention containing amoxicillin and clavulanic acid is advantageous in that (1) the large-scale production is possible as the dispersible tablet is endowed with more compressibility without adherence of the granulated powder to metal machinery parts in a roller compactor, and (2) the dispersible tablet of this invention is rapidly disintegrated and easily dispersed, when immersed in water, to form suspensions.

[83]

Brief Description of the Drawings [84] Fig. 1 shows the results of disintegration test according to different contents of in- tragranular microcrystalline cellulose.

[85] Fig. 2 shows the results of disintegration test according to different contents of ex- tragranular microcrystalline cellulose.

[86]

Best Mode for Carrying Out the Invention

[87] This invention will now be described by reference to the following Examples which are merely illustrative and which are not to be construed as a limitation of the scope of this invention which is defined in particular by the Claims.

[88]

[89] Examples 1-3.

[90] Under the following contents as shown in Table 1, a dispersible tablet were prepared using amoxicillin and clavulanate potassium (4:1), intragranular micro- crystalline cellulose in the amount of 5-15 weight% based on the total granulate weight and extragranular microcrystalline cellulose in the amount of 20-40 weight% based on the total tablet weight.

[91]

[92] Amoxicillin/clavulanate potassium (4:1), microcrystalline cellulose, silicon dioxide and acesulfam potassium (passed through #30 sieve) were mixed. In this mixture, mixture of polacrilin potassium and iron oxide (passed through #100 sieve) was added and mixed, the mixture was further mixed with colloidal silicon dioxide and magnesium stearate (passed through #30 sieve). The mixture was compressed using a roller compressor (Freund Co.) under the following conditions: roller speed (2 rpm), screw speed (14 rpm) and pressure (7 Mpa). Sheets, so obtained, are milled using an oscillator equipped with #16 sieve to obtain an appropriate size of granulate.

[93]

[94] Microcrystalline cellulose and crospovidone was added to the granulate, followed by the addition of mixture of powdered flavor and iron oxide (passed through #100 sieve) and then the mixture was mixed with colloidal silicon dioxide and magnesium stearate (passed through #30 sieve) and tabletted using an automatic tabletting machine (Erweka Co.) to prepare a dispersible tablet.

[95]

[96] Table 1

[97] [98] [99] Examples 4-6. [100] In the same manner as Examples 1-3, a dry granulate was prepared under the following contents as shown in Table 2. Then, microcrystalline cellulose, crospovidone and sodium lauryl sulfate were added to the granulate, followed by the addition of mixture of powdered flavor and iron oxide (passed through #100 sieve). Then the mixture was mixed with colloidal silicon dioxide and sodium stearyl fumarate (passed through #30 sieve) and tabletted using an automatic tabletting machine (Erweka Co.) to prepare a dispersible tablet.

[101] In the same manner as Examples 1-3, a dispersible tablet was prepared using the in- tragranular microcrystalline cellulose in the amount of 5-15 weight% based on the total granulate weight and extragranular microcrystalline cellulose in the amount of 20-40 weight% based on the total tablet weight.

[102] [103] Table

[104] [105] [106] Comparative examples 1-4 [107] In the same manner as Examples 1-3, a dispersible tablet containing amoxicillin and clavulanate potassium (4:1) was prepared under the following contents as shown in Table 3, except that Comparative examples 1-2 employed D-mannitol or lactose instead of microcrystalline cellulose as a diluent, while Comparative examples 3-4 employed copovidone or hydroxypropylmethyl cellulose 2910 as a binder instead of intragranular microcrystalline cellulose,

[108] [109] Table 3

[HO] [111] Comparative examples 5-7. [112] In the same manner as Examples 1-3, a dispersible tablet containing amoxicillin and clavulanate potassium (4:1) was prepared under the following contents as shown in Table 4, except that the amount of intragranular microcrystalline cellulose exceed 15 weight% based on the total granulate weight and extragranular microcrystalline cellulose was present in the amount of less than 20 weight% based on the total tablet weight.

[113] [114] Table 4

[115] [116] Experimental example 1 : Disintegration test [117] Dispersible tablets, so prepared by Examples 4-6 and Comparative examples 2-3, were tested in accordance with the disintegration test method of the Korean Pharmacopoeia (the 8^th revised edition), provided that a purified water of 15-25⁰C was used as a disintegration test media.

[118] As shown in Table 5, all dispersible tablets by Examples 1-6 revealed a rapid disintegration time of less than 60 seconds. By contrast, the disintegration time of all dispersible tablets by Comparative examples 1-4 was in the range of 4-8 minutes, exceeding the specification of disintegration time (3 minutes).

[119] Further, as shown in Figs. 1-2, the significant delay of disintegration time was observed in Comparative examples 5-7, as the amount of intragranular microcrystalline cellulose increased and that of extragranular microcrystalline cellulose decreased.

[120] [121] Table 5

[122] [123] Experimental example 2: Stability test [124] An accelerated testing was performed using dispersible tablets (alu-alu PTP packing), so prepared by Example 1, under the following storage conditions to measure the contents of amoxicillin and clavulanic acid by HPLC.

[125] 1) Storage condition: 4O⁰C, 75% relative humidity [126] 2) Storage period: six months [127] [128] As shown in Table 6, no change in disintegration was observed with time for 6 months, and the contents of amoxicillin and clavulanic acid were in conformity with the specifications.

[129] [130] Table 6

Claims

[1] An oral dispersible tablet comprising amoxicillin and clavulanic acid or its salts including (1) a dry granulate comprising a mixture of amoxicillin and clavulanic acid or its salts as active ingredients, a disintegrant, a lubricant and a diluent, that is prepared by roller compaction in the dry granulation process, and (2) said ex- tragranular ingredients comprising a disintegrant, a lubricant and a diluent, characterized in that:

- said intragranular ingredients include a lubricant and a microcrystalline cellulose in the amounts of 0.5-1.5 weight% and 5-15 weight%, respectively, based on the total granulate weight, and

- said extragranular ingredients include 20-40 weight% of microcrystalline cellulose based on the total tablet weight.

[2] A process for preparing an oral dispersible tablet comprising amoxicillin and clavulanic acid or its salts, characterized by the following two steps of:

(A) preparing a dry granulate by roller compaction process, in which the intragranular ingredients include a mixture of amoxicillin and clavulanic acid or its salts as active ingredients, adisintegrant and a lubricant in the amount of 0.5-1.5 weight% based on the total granulate weight and microcrystalline cellulose in the amount of 5-15 weight% based on the total granulate weight, and

(B) tabletting the dry granulate, so obtained from (A) step, with the extragranular ingredients comprising a disintegrant, a lubricant and microcrystalline cellulose in the amount of 20-40 weight% based on the total tablet weight.