WO2006009333A1

WO2006009333A1 - Cored tablets comprising clavulanate and amoxycilin with multiple film-coated core layer

Info

Publication number: WO2006009333A1
Application number: PCT/KR2004/002120
Authority: WO
Inventors: Ji Hoon Jung; Min Suk Lee; Jeong Hwa Park; Bong Yong Lee
Original assignee: Daewoong Pharmaceutical Co., Ltd.
Priority date: 2004-07-23
Filing date: 2004-08-23
Publication date: 2006-01-26
Also published as: KR100638315B1; KR20060008167A

Abstract

Disclosed are a cored tablet comprising a multiple film coated core layer containing clavulanate and an outer layer containing amoxycillin, and a method of preparing the same.

Description

CORED TABLETS COMPRISING CLAVULANATE AND AMOXYCILLIN WITH MULTIPLE FILM-COATED CORE LAYER

Technical Field

The present invention relates to a cored tablet comprising multiple film-coated clavulanate core layer and an amoxycillin outer layer and a method of preparing the same.

Background Art

Amoxycillin is a drug substance representative of beta-lactam antibiotics the antibacterial activity of which is achieved by inhibiting the synthesis of bacterial walls. Because an antibiotic resistance mechanism of bacteria is conferred by producing beta-lactamase enzymes which destroy the beta-lactam structure of antibiotics, the use of the beta-lactam antibiotic amoxycillin in combination with clavulanate, a beta-lactamase inhibitor, enhances the effectiveness of amoxycillin (GB1508977) . It is also known that clavulanate has an unexpected activity in enhancing the effectiveness of amoxycillin against microorganisms which have an antibiotic resistance mechanism which is different to that mediated by beta-lactamase enzymes (WO 94/16696) . Combined formulations of amoxycillin and clavulanate are now commercially available in various dosage forms such as film tablets, chewing tablets, suspensions, etc., with the predominance of film tablets over other forms. In GB 2005538, there is provided a packed pharmaceutical composition comprising amoxycillin and clavulanate in a weight ratio of amoxycillin:clavulanate between 1:1 to 6:1. Since the disclosure, various packed dosage forms comprising amoxycillin and clavulanate in various weight ratios have been developed.

US 6,051,255 discloses a process for preparing a tablet formulation containing a tablet core, which comprises compacting a mixture of amoxycillin and clavulanate, coating the compact mixture with a film coating selected from among hydroxypropylcellulose, hydroxypropylmethyl cellulose, ethylcellulose, methylhydroxyethylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose and acrylate polymers.

Korean Pat. No. 1999-0087104 discloses a process for preparing a pharmaceutical composition, which comprises tempering amoxycillin paste with liquid, drying the paste to afford support-free coagulates ranging, in average standard particle size, from 100 to l,000μm, and admixing the coagulates with clavulanate by a direct compression technique.

In order to solve the problem with conventional amoxycillin/clavulante tablet formulations which release the active ingredients immediately when they reach the stomach, extensive research has been conducted to develop formulations which are able to release the active ingredients in a controlled manner after administration.

WO 95/20946 discloses a tablet formulation which comprises a first rapid release layer and a second slow release layer, all layers including amoxycillin and optionally clavulanate. An example of this tablet formulation comprises amoxycillin in the first rapid release layer, with the inclusion of amoxycillin and clavulanate in the second slow release layer.

WO 98/05305 describes a bilayered tablet comprising amoxycillin in a first layer and clavulanate in a second layer which further includes trehalose as an expedient for stabilizing the clavulanate. WO 95/28148 discloses a tablet formulation comprising a core which includes amoxycillin and potassium clavulanate, the core being coated with a release retarding coating, the coated core being itself surrounded by a casting layer. With preferential solubility in the environment of the intestine relative to that of the stomach, the release retarding coating sustains the release of the active materials.

As described above, the main topics of the prior arts are to enhance the antibacterial activity of amoxycillin through a cooperation with clavulanate and to control the release of the active materials through the use of coatings.

With high sensitivity to moisture, clavulanate readily undergoes degradation in the presence of water. With reference to antibiotic drug standards according to a notification of the Korea Food and Drug Administration, amoxycillin itself contains moisture in an amount of 11.5 to 14.5%, and potassium clavulanate itself in an amount of 1.5% or less, but a combined material of amoxycillin and potassium clavulanate with a ratio of 2:1 (amoxicilline:potassium clavulanate) in an amount of 7.5 to 9.5 %. Thus, potassium clavulanate, if existing alone with a moisture content of 1.5 % or less, extends in moisture content to 7.5 to 9.5 % when combined with amoxycillin, so that the combined formulation of amoxycillin and potassium clavulanate suffers from a lowered stability upon storage and a decrease in active material content.

Clavulanates, especially potassium clavulanate, are exceptionally difficult to formulate because of their extreme hygroscopicity and moisture sensitivity. Upon contact with water and aqueous media, they are readily degraded. To overcome these drawbacks, much research has been conducted.

WO 97/17960 describes a pharmaceutical composition for oral administration, in the form of, for example, a tablet or granulate formulation, which comprises amoxycillin, clavulanate and a desiccant, wherein the desiccant serves to increase the stability of the composition and comprises a pharmaceutically acceptable desiccating salt such as sodium chloride, calcium chloride, magnesium chloride, etc. Korean Pat. No. 10-2002-0045585, issued to the present applicant, teaches that clavulanate and amoxycillin are incorporated within a core and an outer layer, respectively, so as to prevent the increase of moisture content therein during the formulation of clavulanate and amoxycillin. The patent describes that after being doubly wrapped in press- through packages and then aluminum bags, the core tablets with clavulanate (core) and amoxycillin (outer layer) incorporated separately were found to have the content of clavulate decreased less than were formulations of clavulanate in direct admixture with amoxycillin as measured by an accelerated test in a condition of 40 °C and 75% RH. The cored tablets of clavulanate and amoxycillin incorporated separately are surely improved in stability compared to the formulations of clavulanate in direct admixture with amoxycillin, but there is a need for a cored tablet comprising clavulanate and amoxycillin, in which clavulanate decreases less, that is, has superior stability for long term storage even under non-ideal circumstances, for example, in a non airtight state or in an open package.

Disclosure of the Invention

Leading to the invention, the intensive and thorough research on formulations of amoxycillin and clavulanate, conducted by the present inventors, resulted in finding that when a clavulanate-containing core layer surrounded by an amoxycillin-containing outer layer is coated with a first alcohol-based film coating comprising hydroxypropylmethylcellulose, hydroxypropylcellulose or a mixture thereof and then with a second water-based film coating comprising polyvinylalcohol, polyvinylpyrrolidone or a mixture thereof and optionally with a third water- based film coating comprising carboxymethylcellulose, polyethylene glycol, polypropylene glycol or a mixture thereof, the tablet comprising the core layer can stably maintained for a long period of time in poor circumstances.

Best Mode for Carrying Out the Invention In accordance with an embodiment of the present invention, there is provided a cored tablet consisting of a core layer including multiple film-coated clavulanate and an outer layer including amoxycillin. The term "multiple film coating" as used herein refers to coating the clavulanate-including core layer at least twice, preferably two to five times, and more preferably two or three times, with films of different compositions, and have the same meaning as the term multiple film coating for core.

Clavulanate contained in the cored tablet of the present invention may be in the form of pharmaceutically acceptable organic acid salts, metal salts such as alkaline metal salts or alkali earth metal salts, or esters of clavulanic acid, or salt-like derivatives of organic acid for suppressing gastrointestinal intolerance, such as calcium citrate (WO96/07408) , with preference for alkaline metal salts of clavulanic acid, especially potassium clavulanate.

Amoxycillin suitable for use in the cored tablet of the present invention may be in the form of hydrates, anhydrous amoxycillin, or amoxycillin metal salts. Preferable are amoxycillin hydrates with amoxycillin trihydrate being more preferable. Depending on titers of the active materials, the overall weight of amoxycillin: clavulanate may vary between broad limits, for example, 1:1 to 7:1, preferably between 1:1 to 3:1 and more preferably 2:1. The clavulanate-including core layer and the amoxycillin-including outer layer may comprise pharmaceutically acceptable carriers, such as excipients, binders, disintegrants, lubricants, colorants, and the like.

Any excipients, if pharmaceutically acceptable, may be used in the cored tablets of the present invention. Preferable is the excipient selected from the group consisting of lactose, microcrystalline cellulose, low substituted hydroxypropylcellulose, corn starch, potato starch, wheat starch, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, dextrin, methyl cellulose, and combinations thereof. Preferably, excipients are contained in an amount of 10 to 90 weight % based on the total weight of the tablet.

Common binders well known in the pharmaceutical technology may be used in the cored tablet of the present invention. Suitable is the binder selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, dextrin, gelatin, methylcellulose, hydroxycellulose, hydroxymethylcellulose, polyvinylalcohol, pre-gelatinized starch, Arabic gum, and combinations thereof. Binders are preferably used in an amount of 2 to 40 weight % based on the total weight of the tablet. Any disintegrant well known in the art can be contained in the cored tablet of the present invention. Preferable is a disintegrant selected from the group consisting of sodium starch glycolate, crosspovidone, crosscamellose, low substituted hydroxypropylcellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, calcium carboxymethylcellulose, and combinations thereof. Preferably, the disintegrant may be contained in an amount of 0.1 to 32 weight % based on the total weight of the tablet.

Any lubricant well known in the art can be used in the cored tablet of the present invention. Suitable is lubricant selected from the group consisting of magnesium stearate, talc, stearic acid, anhydrous light silica, and combination thereof. Preferably, the lubricant may be contained in an amount of 0.1 to 20 weight % based on the total weight of the tablet.

One or more colorants, if necessary, may be used in the cored tablet. Their examples comprise titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, and aluminum lake such as dye Blue No. 1 aluminum lake, dye Red No. 40 aluminum lake, dye Yellow No. 203 aluminum lake, etc.

As for the core layer comprising clavulanate in combination with the aforementioned, pharmaceutically acceptable additives, it may be exemplified by a core layer comprising potassium clavulanate, microcrystalline cellulose, calcium carboxymethylcellulose and stearic acid, or a core layer comprising potassium clavulanate, microcrystalline cellulose, hydroxypropylcellulose, anhydrous light silica, and magnesium stearate. An example of the outer layer may comprise amoxycillin trihydrate in combination with microcrystalline cellulose, hydroxypropylcellulose, calcium carboxymethylcellulose and magnesium stearate or in combination with microcrystalline cellulose, hydroxypropylcellulose, anhydrous light silica and magnesium stearate.

In accordance with the present invention, the core layer is coated by multiple film coating to minimize water content therein. A first film coating for the core layer is an alcohol- based coating comprising hydroxypropylmethylcellulose, hydroxypropylcellulose or a combination thereof. As a second film coating, a water-based coating comprising polyvinylalcohol, polyvinylpyrrolidone, or a combination thereof is used.

In a preferred embodiment, there is provided a cored tablet comprising clavulanate and amoxycillin with multiple film coating layers for the core, wherein the core comprises clavulanate and is coated with a first alcohol-based film coating including hydroxypropylmethylcellulose, hydroxypropylcellulose or a combination thereof and a second water-based coating including polyvinyl alcohol, polyvinylpyrrolidone or a combination thereof, the coated core being surrounded by an outer layer comprising amoxycillin.

The first coating, serving as a sub-coating for the second water-based coating, of the clavulanate-comprising core is based on alcohol so that it can be handled at lower temperatures than the second coating can. Additionally, the use of alcohol improves the coating efficiency and avoids the ingress of moisture into the tablet. Particularly, alcohol is advantageous over water in terms of drug stability due to the susceptibility of clavulanate to heat.

Examples of the alcohol suitable for use in the first coating comprise methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol and the like with preference for ethanol. As for the polymer contained in the first coating, hydroxypropylmethylcellulose is more preferable than hydroxypropylcellulose and a mixture of hydroxypropylcellulose and hydroxypropylmethylcellulose.

The second coating for the clavulanate-comprising core acts to prevent moisture ingress, and polyvinyl alcohol, polyvinylpyrrolidone or a mixture of polyvinyl alcohol and polyvinylpyrrolidone is suitable for use in this coating.

Polyvinyl alcohol is more preferably used.

In a preferred embodiment, the clavulanate-comprising core is further coated with a third water-based film coating comprising carboxymethylcellulose, polyethyleneglycol or a mixture thereof after being coated with the first film and the second film coating.

The third coating layer of the clavulanate-comprising core not only provides a smooth skin for the tablet so as to help feed the inner core of the tablet upon pressing, but improves the moisture protection of the second coating layer so as to add safety to the tablet of clavulanate/amoxicillin.

Examples of the polymer used for the third water-based coating comprise carboxymethylcellulose, polyethyleneglycol, propyleneglycol and mixtures thereof, with preference for carboxymethylcellulose.

The celluloses may be used in the form of salts, especially alkali metals such as sodium and potassium. Each of the film coatings of the core may further comprise a colorant or a plasticizer. Additionally, each film coating may comprise polymers such as ethylcellulose, hydroxyethylcellulose, polyethyleneglycol, etc., tablet flow aids such as talc powder, suspending agents such as xanthan gum and Arabic gum, and flavors. These additives may be included alone or in combination.

Examples of the colorant which may be used in the film coatings comprise titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, riboflavin, and aluminum lake. The plasticizer suitable for use in the film coatings can be exemplified by- lecithin, propylene glycol, myvacet (acetylated monoglyceride) , glycerol, glycerin, sorbitol, glycerol triacetate, diethylphthalate, triethylcitrate, dextrin, and dextrose.

In a concrete embodiment of the present invention, the first film coating layer comprises hydroxypropylmethylcellulose, hydroxypropylcellulose or a mixture thereof in an amount of 20 to 70 weight parts, preferably in an amount of 45 to 60 weight parts and more preferably in an amount of 55 weight parts; titanium dioxide, magnesium carbonate, calcium sulfate, magnesium oxide or aluminum hydroxide in an amount of 10 to 50 weight parts, preferably in an amount of 15 to 30 weight parts and more preferably in an amount of 23 weight parts; ethylcellulose, hydroxyethylcellulose or a mixture thereof in an amount of 5 to 30 weight parts, preferably in an amount of 10 to 20 weight parts and more particularly in an amount of 14 weight parts; and diethylphthalate, lecithin, triethylcitrate, propylene glycol, glycerin, polyethylene glycol or a mixture thereof in an amount of 1 to 30 weight parts, preferably in an amount of 3 to 10 weight parts and more preferably in an amount of 8 weight parts, based on the total weight of the first film coating layer.

In a preferred concrete embodiment of the present invention, the first film coating layer comprises hydroxypropylmethylcellulose, titanium dioxide, ethylcellulose and diethylphthalate in the amounts mentioned above, respectively.

In another concrete embodiment of the present invention, the second film coating layer comprises polyvinylalcohol, polyvinylpyrrolidone or a mixture thereof in an amount of 20 to 70 weight parts, particularly in an amount of 30 to 50 weight parts and more particularly in an amount of 45 weight parts, titanium dioxide, magnesium carbonate, calcium sulfate, magnesium oxide or aluminum hydroxide in an amount of 10 to 50 weight parts, preferably in an amount of 25 to 40 weight parts, and more particularly in an amount of 32 weight parts; talc or magnesium stearate in an amount of 5 to 30 weight parts, preferably in an amount of 15 to 25 weight parts and more particularly in an amount of 20 weight parts; and lecithine, triethylcitrate, propylene glycol, glycerin, polyethylene glycol or a mixture thereof in an amount of 1 to 30 weight parts, preferably in an amount of 1 to 5 weight parts and more particularly in an amount of 3 weight parts, based on the total weight of the second film coating layer.

In anther preferred concrete embodiment of the present invention, the second film coating layer comprises polyvinyl alcohol, titanium dioxide, talc and lecithin.

In a further concrete embodiment of the present invention, the third film coating layer comprises carboxymethylcellulose, polyethylene glycol, propylene glycol or a mixture thereof in an amount of 20 to 70 weight parts, preferably in an amount of 40 to 60 weight parts, and more preferably in an amount of 55 weight parts; and dextrin, dextrose monohydrate, lecithin or a mixture thereof in an amount of 1 to 50 weight parts, preferably in an amount of 30 to 50 weight parts and more preferably in an amount of 45 weight parts, based on the total weight of the third film coating layer. In a further preferred concrete embodiment of the present invention, the third film coating layer comprises sodium carboxymethylcellulose, dextrin, dextrose monohydrate and lecithin. Based on the total weight of the tablet, the multi film coating layers for the clavulanate-comprising core are present in an amount of 2 to 20 weight parts, preferably in an amount of 5 to 10 weight parts and more preferably in an amount of 8.5 weight parts. In a further preferred embodiment of the present invention, the amoxycillin-comprising outer layer is coated with a film coating. Preferably, the outer layer is coated with an alcohol-based coating comprising one selected from among cellulose polymers, for example, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, ethylcellulose, carboxymethylethylcellulose and polyethylene glycol, methacrylic acid copolymers and combinations thereof and may further comprise plasticizers and colorants as described above. A concrete example of the film coating for the outer layer is given by a combination of hydroxypropylmethycellulose, titanium dioxide, talc and polyethylene, a combination of hydroxypropylmethylcellulose, titanium dioxide, ethylcellulose and diethylphthalate, or a combination of hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate and polyethylene glycol.

Based on the total weight of the tablet, the film coating for the outer layer is present in an amount of 2 to 20 weight parts, preferably in an amount of 5 to 10 weight parts, and most preferably in an amount of 6 weight parts.

In accordance with yet another embodiment of the present invention, there is provided a method of preparing a cored tablet of clavulanate and amoxycillin with multiple film coatings, which comprises pressing clavulanate in an admixture with a pharmaceutically acceptable carrier to afford a core, coating the core with multiple film coatings, and adding the coated core to amoxicillin in an admixture with a pharmaceutically acceptable carrier and pressing the mixture to give an outer layer.

In the method, the coating step can be achieved by coating the core with a first alcohol-based film comprising hydroxypropylmethylcellulose, hydroxypropylcellulose or a mixture thereof and then with a second water-based film comprising polyvinylalcohol, polyvinylpyrrolidone or a mixture thereof.

According to a preferred embodiment of the present invention, there is provided a method of preparing a cored tablet of clavulanate and amoxycillin with multiple film coatings for a core, which comprises (1) pressing clavulanate in an admixture with a pharmaceutically acceptable carrier to afford a core, (2) coating the core with a first alcohol- based film coating comprising hydroxypropylmethylcellulose, hydroxypropylcellulose or a mixture thereof and then with a second film water-based coating comprising polyvinylalcohol, polyvinylpyrrolidone or a mixture thereof; and (3) mixing the coated core of step (2) and amoxycillin in an admixture with a pharmaceutically acceptable carrier and pressing the mixture to produce an outer layer.

In yet another preferred embodiment, the method of the present invention further comprises coating the second film- coated core of step (2) with a third water-based coating film comprising carboxymethylcellulose, polyethylene glycol, propylene glycol or a mixture thereof.

In still another preferred embodiment, the method of the present invention further comprises coating the outer layer of step (3) with a film. This film coating may be an alcohol-based coating comprising a cellulose polymer, such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, ethylcellulose and carboxymethylethylcellulose, polyethylene glycol, methacrylic acid copolymer or a mixture thereof, and may further comprise a plasticizer and/or a colorant.

Using a conventional mixer, clavulanate or amoxycillin may be mixed with a pharmaceutically acceptable carrier in a dry manner and the mixture may be compressed in a rotary press to give a tablet. The film coating of the core layer may be achieved with various coating machines such as a conventional fan, a high coater, a fluid bed coater and the like, and preferably with a high coater. The multiple film-coated cored tablets according to the present invention maintain great stability for a long period of time even under poor circumstances, e.g., even when their packages are torn open. Compared not only with a conventional combined tablet of clavulanate in admixture of amoxycillin but also with cored tablets with mono film coating for a core, the cored tablets with multiple film coatings for a core according to the present invention are much more stable. Data shown in Table 1 reveals that the cored tablets with multiple film coating for the core according to the present invention are superior in stability under high temperature and humidity conditions compared to cored tablets with mono film coating for core when they are in HDPE value packs, as measured by an accelerated test. Particularly, even when the HDPE value packs are unsealed, the cored tablets with multiple film coated cores

(clavulanate content: about 93% or more) of the present invention show much higher stability over the cored tablets with mono film coated core (clavulanate content: 83.5%) as seen in Table 2. In fact, because the ingestion of packed medicinal tablets requires their exposure to the air, the stability maintenance regardless of package states is a very important factor to determine product stability.

The dosage amounts of clavulanate and amoxycillin may be determined according to gastrointestinal absorptivity, inactivity rate, excretion rate, age, sex and condition of patient, disease severity, etc. For example, a unit dosage form comprising amoxycillin 250 mg and clavulanate 125 mg may be administered to an adult three times a day.

Although the preferred embodiments of the present invention will be disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

EXAMPLES EXAMPLE 1 A. Preparation of core layer comprising clavulanate

(1) preparation of core layer

core layer (154mg per tablet) potassium clavulanate(in titer) 125.Omg microcrystalline cellulose 20.Omg hydroxypropylcellulose 2.Omg calcium carboxymethylcellulose 5.Omg magnesium stearate 2.Omg

All of the above components, except for magnesium stearate, were blended for 20 min in a V-type mixer and compacted on a roller compactor (Sejong Pharmatech Co. Ltd.) utilizing a roller speed of 5-10 rpm and a screw-feeder speed of 5-10 rpm. The ribbons thus obtained were sieved through a screen with #12 to #16 meshes. Magnesium stearate was added to the granules thus produced and the resulting mixture was blended for an additional five minutes. The granules were compressed on a rotary-type Killian tablet press at a speed of 10 to 30 rpm.

(2) First film coating of core layer

hydroxypropylmethylcellulose 5.5mg titanium dioxide 2.3mg ^•ethylcellulose 1.4mg diethylphthalate 0.8mg

All of the above components were added to 124mg of ethanol to give a film coating solution with which the clavulanate core layer prepared in A-(I) of Example 1 was coated at 25-30 °C and 27% or less RH by use of a HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and an air pressure of 6-7 bar to prepare a film-coated clavulanate core layer.

(3) second film coating of core layer

polyvinyl alcohol 4.5mg titanium dioxide 3.2mg talc 2.0mg lecithin 0.3mg

All of the above components were added to 45mg of filtered water to give a film coating solution with which the coated clavulanate core layer obtained in A- (2) of Example 1 was further coated at 50 to 55 ⁰C in 27% or less RH by use of HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and an air pressure of 6-7 bar to prepare a double film- coated clavulanate core layer. B. Preparation of outer layer comprising amoxycillin

(1) preparation of outer layer

outer layer (308mg per tablet) amoxycillin trihydrate (in titer) 250.Omg microcrystalline cellulose 40.Omg hydroxypropyl cellulose 4.Omg calcium carboxymethylcellulose 10.Omg magnesium stearate 4.Omg

All of the above components, except for magnesium stearate, were blended for 20 min in a V-type mixer and compacted on a roller compactor (Sejong Pharmatech Co. Ltd.) utilizing a roller speed of 5-10 rpm and a screw-feeder speed of 5-10 rpm. The ribbons thus obtained were sieved through a screen with #12 to #16 meshes. Magnesium stearate was added to the granulates thus produced and the resulting mixture was blended for an additional five minutes. The granulates were blended with the clavulate core layer prepared in A of

Example 1 and the blend was compressed at a rotary disc speed of 10 to 30 rpm to produce cored tablets comprising a core layer.

(2) film coating of outer layer hydroxypropylmethylcellulose 20.Omg titanium dioxide 4.Omg talc 8.Omg polyethylene glycol 6000 2.Omg

All of the above components were added to 420 mg of ethanol to give a film coating solution with which the coated clavulanate core layer obtained in B-(I) of Example 1 was further coated at 25 to 30 ⁰C in 27% or less RH by use of HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and an air pressure of 6-7 bar to prepare a cored tablet with film coatings for the core

EXAMPLE 2

A. Preparation of core layer comprising clavulanate

(1) preparation of core layer

A core layer was prepared in the same manner as described in Example 1

(2) first film coating of core layer

hydroxypropylmethylcellulose 5.5mg titanium dioxide 2.3mg ethylcellulose 1.4mg diethylphthalate 0.8mg

All of the above components were added to 124 mg of ethanol to give a film coating solution with which the coated clavulanate core layer obtained in A-(I) of Example 2 was further coated at 25-30 ⁰C in 27% or less RH by use of HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and air pressure of 6-7 bar to prepare a film coated clavulanate core layer.

(3) second film coating of core layer

polyvinyl alcohol 4.5mg titanium dioxide 3.2mg talc 2.0mg lecithin 0.3mg

All of the above components were added to 45 mg of filtered water to give a film coating solution with which the coated clavulanate core layer obtained in A- (2) of Example 2 was further coated at 50 to 55 ⁰C in 27% or less RH by use of HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and air pressure of 6-7 bar to prepare a double film-coated clavulanate core layer.

(4) third film coating of core layer

sodium carboxymethylcellulose 0.25mg dextrin 0.lmg dextrose monohydrate 0.lmg lecithin 0.05mg

All of the above components were added to 9.5 mg of filtered water to give a film coating solution with which the coated clavulanate core layer obtained in A-(3) of Example 2 was further coated at 50 to 55 ⁰C in 27% or less RH by use of HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and air pressure of 6-7 bar to prepare a triple film coated clavulanate core layer.

B. preparation of outer layer comprising amoxycillin

An outer layer was prepared in the same manner as described in Example 1.

EXAMPLE 3

A. preparation of core layer comprising clavulanate (1) preparation of core layer

A core layer was prepared in the same manner as described in Example 1.

(2) first film coating of core layer

hydroxypropylcellulose 5.6mg titanium dioxide 2.4mg ethylcellulose 1.3mg polyethylene glycol 6000 0.7mg

All of the above components were added to 124 mg of ethanol to give a film coating solution with which the coated clavulanate core layer obtained in A-(I) of Example 3 was further coated at 25 to 30 ⁰C in 27% or less RH by use of

HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and air pressure of 6-7 bar to prepare a film coated clavulanate core layer.

(3) second film coating of core layer

polyvinylpyrrolidone 4.3mg titanium dioxide 3.4mg magnesium stearate 1.9mg lecithin 0.3mg xanthan gum 0.lmg

All of the above components were added to 45 mg of filtered water to give a film coating solution with which the coated clavulanate core layer obtained in A-(2) of Example 3 was further coated at 50 to 55°C in 27% or less RH by use of HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and air pressure of 6-7 bar to prepare a double film coated clavulanate core layer.

(4) third film coating of core layer

sodium carboxymethylcellulose 0.45mg polyethylene glycol 6000 0.03mg propylene glycol 0.02mg

All of the above components were added to 10 mg of filtered water to give a film coating solution with which the coated clavulanate core layer obtained in A-(3) of Example 3 was further coated at 50 to 55°C in 27% or less RH by use of

HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and air pressure of 6-7 bar to prepare a triple film coated clavulanate core layer. B. preparation of outer layer comprising amoxycillin

An outer layer was prepared in the same manner as described in Example 1.

EXAMPLE 4

A. Preparation of core layer comprising clavulanate

(1) preparation of core layer

A core layer was prepared in the same manner as described in Example 1.

(2) first film coating of core layer

hydroxypropylmethylcellulose 5.4mg magnesium oxide 2.4mg hydroxyethylcellulose 1.3mg lecithin 0.9mg

All of the above components were added to 124 mg of ethanol to give a film coating solution with which the coated clavulanate core layer obtained in A-(I) of Example 4 was further coated at 25 to 3O⁰C in 27% or less RH by use of HCT-

48 coater (Freund) with a fan rotation speed of 4-5 rpm and air pressure of 6-7 bar to prepare a film coated clavulanate core layer.

(3) second film coating of core layer

polyvinylpyrrolidone 4.5mg aluminum hydroxide 3.2mg talc 2.0mg glycerin 0.3mg

All of the above components were added to 45 mg of filtered water to give a film coating solution with which the coated clavulanate core layer obtained in A- (2) of Example 4 was further coated at 50 to 55°C in 27% or less RH by use of HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and air pressure of 6-7 bar to prepare a double film coated clavulanate core layer.

(4) third film coating of core layer

polyethylene glycol 6000 0.42mg lecithin 0.08mg

Both of the above components were added to 9.5 mg of filtered water to give a film coating solution with which the coated clavulanate core layer obtained in A-(3) of Example 4 was further coated at 50 to 55°C in 27% or less RH by use of HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and an air pressure of 6-7 bar to prepare a triple film coated clavulanate core layer.

B. Preparation of outer layer comprising amoxycillin

An outer layer was prepared in the same manner as described in Example 1.

COMPARATIVE EXAMPLE 1 A. Preparation of core layer comprising clavulanate (1) preparation of core layer

core layer (154mg per tablet) potassium clavulanate (in titer) 125.Omg microcrystallinecellulose 20.Omg hydroxypropylcellulose 2.Omg calcium carboxymethylcellulose 5.Omg magnesium stearate 2.Omg

All of the above components, except for magnesium stearate, were blended for 20 min in a V-type mixer and compacted on a roller compactor (Sejong Pharmatech Co. Ltd.) utilizing a roller speed of 5-10 rpm and a screw-feeder speed of 5-10 rpm. The ribbons thus obtained were sieved through a screen with #12 to #16 meshes. Magnesium stearate was added to the granules thus produced and the resulting mixture was blended for an additional five minutes. The granules were compressed on a rotary-type Killian tablet press in a speed of 10 to 30 rpm.

(2) film coating of core layer

All of the above components were added to 124 mg of ethanol to give a film coating solution with which the clavulanate core layer obtained in A-(I) of Comparative Example 1 was coated at 25 to 30⁰C in 27% or less RH by use of HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and an air pressure of 6-7 bar to prepare a film coated clavulanate core layer.

B. Preparation of amoxycillin outer layer (1) preparation of outer layer outer layer (308mg per tablet) amoxycillin trihydrate (in titer) 250.Omg microcrystallinecellulose 40.Omg hydroxypropylcellulose 4.Omg calcium carboxymethylcellulose 10.Omg magnesium stearate 4.Omg

All of the above components, except for magnesium stearate, were blended for 20 min in a V-type mixer and compacted on a roller compactor (Sejong Pharmatech Co. Ltd.) utilizing a roller speed of 5-10 rpm and a screw-feeder speed of 5-10 rpm. The ribbons thus obtained were sieved through a screen with #12 to #16 meshes. Magnesium stearate was added to the granules thus produced and the resulting mixture was blended for an additional five minutes. The granules were blended with the clavulate core layer prepared in A of Comparative Example 1 and the blend was compressed at a rotary disc speed of 10 to 30 rpm to produce cored tablets comprising a core layer.

(2) film coating of outer layer

hydroxypropylmethylcellulose 20.Omg titanium dioxide 4.Omg talc 8.Omg polyethylene glycolβOOO 2.Omg

All of the above components were added to 420 mg of ethanol to give a film coating solution with which the clavulanate core layer obtained in B-(I) of Comparative Example 1 was coated at 25 to 30°C in 27% or less RH by use of HCT-48 coater (Freund) with a fan rotation speed of 4-5 rpm and air pressure of 6-7 bar to prepare a core tablet with a film coating for a core.

TEST EXAMPLE 1: Test for Stability of Clavulanate and Amoxycillin

20 tablets prepared in each of Examples 1 and 2 and Comparative Example 1 were packed in a value pack made from HDPE (high density polyethylene) and subjected to an accelerated test in which they were stored at 4O⁰C, 75%RH. Thereafter, a measurement was made of the contents of clavulanate and amoxycillin in the tablets (Table 1) .

In addition, after being put in unsealed value packs made from HDPE, the prepared tablets from Examples 1 and 2 and Comparative Example 1 were stored at 25°C and 60% RH and tested for stability (Table 2) . Each sample was measured for the content of clavulanate and amoxycillin. The measurement conditions was as follows:

1) column: Capcel-pak C18 UG120 (4.6mm X 25cm, 5μ, Shiseido) 2) mobile phase: buffer* : MeOH = 95 : 5

*buffer: 6.3 g of ammonium formate was added to water to make exactly IL.

3) flow rate: lmL/min

4) detection wavelength: UV absorption spectrometer (230nm)

Average contents of clavulanate and amoxycillin are given in Tables 1 and 2, below.

TABLE 1

Contents of clavulanate and amoxycillin during storage in

After four months storage, as seen in Table 1, clavulanate remained in the amount of 95.8% in the cored tablet of Example 1 and in the amount of 97.2 % in the cored tablet of Example 2. In contrast, the content of clavulanate in the cored tablet of Comparative Example 1 was greatly reduced, to 93.5 %, after four months' storage, compared with those of Examples 1 and 2.

As for amoxycillin, its contents in the cored tablets of Examples 1 and 2 and Comparative Example 1 after four months storage were comparable with one another, as being detected to be 97.5%, 98.2% and 97.6%, respectively.

TABLE 2

Contents of clavulanate and amoxycillin during storage in unsealed HDPE packs (%)

4 83.5 92.8 96.2

Initial 100 .7 100 .3 101 .4

1 99. 6 99. 9 100 .5

Amoxycillin

2 99. 4 99. 4 100 .3

4 98. 8 99. 0 99. 7

After four weeks storage, as seen in Table 2, clavulanate remained in the amount of 92.8% in the cored tablet of Example 1 and the amount of 96.2% in the cored tablet of Example 2. In contrast, the content of clavulanate in the cored tablet of Comparative Example 1 was greatly reduced to 83.5%. As for amoxicilline, its contents in the cored tablets of both, after four months storage, were not greatly reduced.

Taken together, the data obtained above show that core tablets with double or triple film coatings for core and a tablet formulation with a mono film coating are all stably maintained in value packs, but the former tablets are much more stable than the latter when the value packs are torn open.

In practice, even though tablet products are packed before distribution, the pack must be torn open in order to use the tablets, so that the stability in naked state has a great influence on the utility of the products. Accordingly, the cored tablets with double or triple film coatings for the core according to the present invention are more valuable for practical use than conventional cored tablets with mono film coating.

INDUSTRIAL APPLICABILITY

The cored table comprising a core layer of clavulanate and an outer layer of amoxycillin in which the core layer is multiple film coated according to the present invention efficiently blocks the ingress of moisture into the clavulanate core for a long period of time, even in poor circumstances, and thus exhibits excellent stability.

Claims

1. A cored tablet of clavulanate and amoxycillin with

multiple film coating layers for a core, comprising a

clavulanate-containing core surrounded by an amoxycillin-

containing outer layer, the core being coated with a first

alcohol-based film coating comprising hydroxypropylmethyl

cellulose, hydroxypropylcellulose or a mixture thereof, and

with a second water-based film coating comprising

polyvinylalcohol, polyvinylpyrrolidone or a mixture thereof.

2. The cored tablet of clavulanate and amoxycillin with multiple film coating layers for the core as set forth in claim 1, wherein the core is further coated with a third water-based film coating comprising carboxymethylcellulose, polyethylene glycol, propylene glycol or a mixture thereof.

3. The cored tablet of clavulanate and amoxycillin with multiple coating layers for the core as set forth in claim 1 or 2, wherein the amoxycillin-containing outer layer is film coated.

4. The cored tablet of clavulanate and amoxycillin with multiple coating layers for the core as set forth in claim 1, wherein the first alcohol-based film coating is based on ethanol.

5. The cored tablet of clavulanate and amoxycillin with multiple coating layers for the core as set forth in claim 1 or 2, wherein the film coating for the core further comprises a colorant, a plasticizer, or a mixture thereof.

6. The cored tablet of clavulanate and amoxycillin with multiple coating layers for the core as set forth in claim 5, wherein the plasticizer is selected from the group consisting of lecithin, propylene glycol, myvacet, glycerol, glycerin, sorbitol, glycerol triacetate, diethylphthalate, triethylcitrate, dextrin, dextrose and mixtures thereof.

7. The cored tablet of clavulanate and amoxycillin with multiple coating layers for the core as set forth in claim 5, wherein the colorant is selected from the group consisting of titanium dioxide, iron oxide, magnesium carbonate, potassium sulfate, magnesium oxide, and magnesium hydroxide.

8. The cored tablet of clavulanate and amoxycillin with multiple coating layers for the core as set forth in claim 1, wherein the first film coating comprises hydroxypropylmethylcellulose, titanium dioxide, ethylcellulose and diethylphthalate.

9. The cored tablet of clavulanate and amoxycillin with multiple coating layers for the core as set forth in claim 1, wherein the second film coating comprises polyvinylalcohol, titanium dioxide, talc and lecithin.

10. The cored tablet of clavulanate and amoxycillin with multiple coating layers for the core as set forth in claim 2, wherein the third film coating comprises sodium carboxymethylcellulose, dextrin, dextrose monohydrate and lecithin.

11. A method of preparing the cored tablet of claim 1, comprising:

(1) pressing clavulanate in admixture with a pharmaceutically acceptable carrier to produce a core;

(2) coating the core of step (1) with a first alcohol- based coating comprising ' hydroxypropylmethylcellulose, hydroxypropylcellulose or a mixture thereof and then with a second water-based coating comprising polyvinylalcohol, polyvinylpyrrolidone or a mixture thereof; and

(3) Adding the coated core of step (2) to amoxycillin in admixture with a pharmaceutically acceptable carrier and pressing the mixture to produce an outer layer. .

12. The method as set forth in claim 11, wherein the coating step further comprises coating the coated core of step (2) with a third water-based coating comprising carboxymethyl cellulose, polyethylene glycol, propylene glycol or a mixture thereof.

13. The method as set forth in claim 11 or 12, further comprising coating the outer layer of step (3) with a film coating.

14. The method as set forth in claim 11, further comprising compacting in a dry manner clavulanate in an admixture with a pharmaceutically acceptable carrier before step (1) and compacting in a dry manner the amoxycillin in an admixture with a pharmaceutically carrier before step (3) .