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WO2006009333A1 - Comprimes creux comprenant le clavulanate et l'amoxyciline avec plusieurs couches centrales enrobees d'un film - Google Patents

Comprimes creux comprenant le clavulanate et l'amoxyciline avec plusieurs couches centrales enrobees d'un film Download PDF

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Publication number
WO2006009333A1
WO2006009333A1 PCT/KR2004/002120 KR2004002120W WO2006009333A1 WO 2006009333 A1 WO2006009333 A1 WO 2006009333A1 KR 2004002120 W KR2004002120 W KR 2004002120W WO 2006009333 A1 WO2006009333 A1 WO 2006009333A1
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WO
WIPO (PCT)
Prior art keywords
clavulanate
core
amoxycillin
coating
film coating
Prior art date
Application number
PCT/KR2004/002120
Other languages
English (en)
Inventor
Ji Hoon Jung
Min Suk Lee
Jeong Hwa Park
Bong Yong Lee
Original Assignee
Daewoong Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daewoong Pharmaceutical Co., Ltd. filed Critical Daewoong Pharmaceutical Co., Ltd.
Publication of WO2006009333A1 publication Critical patent/WO2006009333A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • 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.
  • 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.
  • 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,000 ⁇ m, and admixing the coagulates with clavulanate by a direct compression technique.
  • 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.
  • 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.
  • 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 %.
  • 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.
  • a cored tablet consisting of a core layer including multiple film-coated clavulanate and an outer layer including amoxycillin.
  • multiple film coating 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.
  • organic acid 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.
  • 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.
  • excipients if pharmaceutically acceptable, may be used in the cored tablets of the present invention.
  • 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.
  • excipients are contained in an amount of 10 to 90 weight % based on the total weight of the tablet.
  • 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.
  • 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.
  • the disintegrant may be contained in an amount of 0.1 to 32 weight % based on the total weight of the tablet.
  • lubricant selected from the group consisting of magnesium stearate, talc, stearic acid, anhydrous light silica, and combination thereof.
  • 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 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.
  • 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.
  • 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.
  • a second film coating a water-based coating comprising polyvinylalcohol, polyvinylpyrrolidone, or a combination thereof is used.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • the first film coating layer comprises hydroxypropylmethylcellulose, titanium dioxide, ethylcellulose and diethylphthalate in the amounts mentioned above, respectively.
  • 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.
  • the second film coating layer comprises polyvinyl alcohol, titanium dioxide, talc and lecithin.
  • 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.
  • the third film coating layer comprises sodium carboxymethylcellulose, dextrin, dextrose monohydrate and lecithin.
  • 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.
  • the amoxycillin-comprising outer layer is coated with a film coating.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • a unit dosage form comprising amoxycillin 250 mg and clavulanate 125 mg may be administered to an adult three times a day.
  • polyvinyl alcohol 4.5mg titanium dioxide 3.2mg talc 2.0mg lecithin 0.3mg
  • amoxycillin trihydrate 250.Omg microcrystalline cellulose 40.Omg hydroxypropyl cellulose 4.Omg calcium carboxymethylcellulose 10.Omg magnesium stearate 4.Omg
  • 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.
  • a core layer was prepared in the same manner as described in Example 1
  • polyvinyl alcohol 4.5mg titanium dioxide 3.2mg talc 2.0mg lecithin 0.3mg
  • An outer layer was prepared in the same manner as described in Example 1.
  • a core layer was prepared in the same manner as described in Example 1.
  • 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.
  • 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.
  • An outer layer was prepared in the same manner as described in Example 1.
  • a core layer was prepared in the same manner as described in Example 1.
  • polyvinylpyrrolidone 4.5mg aluminum hydroxide 3.2mg talc 2.0mg glycerin 0.3mg
  • 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.
  • An outer layer was prepared in the same manner as described in Example 1.
  • 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
  • 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.
  • the pack 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.
  • 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.

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Abstract

L'invention porte sur un comprimé creux comprenant plusieurs couches centrales enrobées d'un film et contenant le clavulanate et une couche externe contenant l'amoxycilline, et sur un procédé de préparation de ce comprimé.
PCT/KR2004/002120 2004-07-23 2004-08-23 Comprimes creux comprenant le clavulanate et l'amoxyciline avec plusieurs couches centrales enrobees d'un film WO2006009333A1 (fr)

Applications Claiming Priority (2)

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KR10-2004-0057864 2004-07-23
KR1020040057864A KR100638315B1 (ko) 2004-07-23 2004-07-23 다중 필름 코팅된 코어층을 갖는 클라불라네이트 및아목시실린-함유 유핵정

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WO2013057569A3 (fr) * 2011-10-19 2013-07-04 Micro Labs Limited Composition pharmaceutique à libération prolongée contenant de l'amoxicilline et de l'acide clavulanique
CN103316056A (zh) * 2013-06-24 2013-09-25 江苏鹏鹞药业有限公司 一种板蓝根包衣分散片及其制备方法

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KR102103530B1 (ko) * 2018-06-29 2020-04-22 주식회사 코피텍 필름 코팅용 조성물 및 이를 코팅한 정제
KR102149020B1 (ko) * 2018-11-20 2020-08-28 주식회사 코피텍 높은 방습성을 가지는 필름코팅정
KR102148374B1 (ko) * 2018-11-21 2020-08-27 삼익제약주식회사 콜린알포세레이트를 포함하는 이층 코팅 정제 및 이의 제조 방법

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EP0080862A1 (fr) * 1981-12-02 1983-06-08 Beecham Group Plc Préparation pharmaceutique contenant des antibiotiques béta-lactame
WO1995020946A1 (fr) * 1994-02-04 1995-08-10 Smithkline Beecham Plc Comprimes de type bi-couche a base d'amoxycilline
US6136345A (en) * 1994-04-14 2000-10-24 Smithkline Beecham P.L.C. Tablet containing a coated core
US6051255A (en) * 1994-04-23 2000-04-18 Smithkline Beecham Plc Polymer coated tablet comprising amoxycillin and clavulanate
KR20040012170A (ko) * 2002-08-01 2004-02-11 주식회사 대웅 아목시실린 및 클라불라네이트를 함유하는 유핵정

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013057569A3 (fr) * 2011-10-19 2013-07-04 Micro Labs Limited Composition pharmaceutique à libération prolongée contenant de l'amoxicilline et de l'acide clavulanique
CN103316056A (zh) * 2013-06-24 2013-09-25 江苏鹏鹞药业有限公司 一种板蓝根包衣分散片及其制备方法

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